NM_001018115.3:c.577A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001018115.3(FANCD2):c.577A>G(p.Thr193Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,614,062 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 9 hom., cov: 31)

Exomes 𝑓: 0.0027 ( 97 hom. )

Consequence

FANCD2
NM_001018115.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 2.45

Publications

13 publications found

Variant links:

Genes affected

FANCD2 (HGNC:3585): (FA complementation group D2) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group D2. This protein is monoubiquinated in response to DNA damage, resulting in its localization to nuclear foci with other proteins (BRCA1 AND BRCA2) involved in homology-directed DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

FANCD2 Gene-Disease associations (from GenCC):

Fanconi anemia complementation group D2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003047973).

BP6

Variant 3-10039727-A-G is Benign according to our data. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10039727-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 134328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00214 (325/152204) while in subpopulation SAS AF = 0.0421 (203/4818). AF 95% confidence interval is 0.0374. There are 9 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3 link	c.577A>G	p.Thr193Ala	missense_variant	Exon 9 of 44	ENST00000675286.1	NP_001018125.1	Q9BXW9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1 link	c.577A>G	p.Thr193Ala	missense_variant	Exon 9 of 44		NM_001018115.3	ENSP00000502379.1		Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

326

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0156

Gnomad SAS

AF:

0.0423

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00597

AC:

1501

AN:

251396

AF XY:

0.00741

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0165

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000466

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00274

AC:

4012

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

2683

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000268

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26136

East Asian (EAS)

AF:

0.00952

AC:

378

AN:

39698

South Asian (SAS)

AF:

0.0356

AC:

3067

AN:

86248

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00486

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000238

AC:

265

AN:

1112004

Other (OTH)

AF:

0.00401

AC:

242

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

201

401

602

802

1003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00214

AC:

325

AN:

152204

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

219

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41542

American (AMR)

AF:

0.000131

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.0156

AC:

AN:

5178

South Asian (SAS)

AF:

0.0421

AC:

203

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68004

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000883

Hom.:

Bravo

AF:

0.00117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00633

AC:

769

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group D2

Benign:3

Nov 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Fanconi anemia

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;T;T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.044

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.70

T;T;.;T

MetaRNN

Benign

0.0030

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

L;L;L;L

PhyloP100

2.4

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.93

N;N;N;D

REVEL

Benign

0.13

Sift

Benign

0.49

T;T;T;T

Sift4G

Benign

0.35

T;T;T;D

Polyphen

0.23, 1.0

.;B;B;D

Vest4

0.21

MVP

0.67

MPC

0.15

ClinPred

0.018

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.12

gMVP

0.17

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over