16-89769915-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000135.4(FANCA):c.2426G>A(p.Gly809Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,613,742 control chromosomes in the GnomAD database, including 136,475 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G809V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.47 ( 19562 hom., cov: 32)

Exomes 𝑓: 0.37 ( 116913 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:11O:1

Conservation

PhyloP100: 0.0770

Publications

91 publications found

Variant links:

Genes affected

FANCA (HGNC:3582): (FA complementation group A) 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 A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

FANCA Gene-Disease associations (from GenCC):

Fanconi anemia complementation group A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 16-89769915-C-T is Benign according to our data. Variant chr16-89769915-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.2426G>A	p.Gly809Asp	missense_variant	Exon 26 of 43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.2426G>A	p.Gly809Asp	missense_variant	Exon 26 of 43		NP_001273096.1	O15360-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.2426G>A	p.Gly809Asp	missense_variant	Exon 26 of 43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.472

AC:

71730

AN:

151896

Hom.:

19532

Cov.:

show subpopulations

Gnomad AFR

AF:

0.662

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.524

Gnomad ASJ

AF:

0.254

Gnomad EAS

AF:

0.981

Gnomad SAS

AF:

0.623

Gnomad FIN

AF:

0.414

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.431

GnomAD2 exomes

AF:

0.473

AC:

118634

AN:

250996

AF XY:

0.461

show subpopulations

Gnomad AFR exome

AF:

0.676

Gnomad AMR exome

AF:

0.653

Gnomad ASJ exome

AF:

0.256

Gnomad EAS exome

AF:

0.985

Gnomad FIN exome

AF:

0.409

Gnomad NFE exome

AF:

0.309

Gnomad OTH exome

AF:

0.408

GnomAD4 exome

AF:

0.372

AC:

544336

AN:

1461732

Hom.:

116913

Cov.:

AF XY:

0.376

AC XY:

273703

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.678

AC:

22688

AN:

33476

American (AMR)

AF:

0.636

AC:

28447

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6686

AN:

26136

East Asian (EAS)

AF:

0.980

AC:

38922

AN:

39698

South Asian (SAS)

AF:

0.587

AC:

50627

AN:

86254

European-Finnish (FIN)

AF:

0.404

AC:

21539

AN:

53360

Middle Eastern (MID)

AF:

0.322

AC:

1860

AN:

5768

European-Non Finnish (NFE)

AF:

0.314

AC:

349350

AN:

1111930

Other (OTH)

AF:

0.401

AC:

24217

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

19973

39946

59919

79892

99865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11938

23876

35814

47752

59690

<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:

0.472

AC:

71822

AN:

152010

Hom.:

19562

Cov.:

AF XY:

0.485

AC XY:

36049

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.662

AC:

27445

AN:

41442

American (AMR)

AF:

0.524

AC:

8001

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.254

AC:

882

AN:

3470

East Asian (EAS)

AF:

0.981

AC:

5065

AN:

5162

South Asian (SAS)

AF:

0.623

AC:

3002

AN:

4820

European-Finnish (FIN)

AF:

0.414

AC:

4367

AN:

10560

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.321

AC:

21839

AN:

67970

Other (OTH)

AF:

0.437

AC:

921

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1673

3346

5018

6691

8364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

624

1248

1872

2496

3120

<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:

0.368

Hom.:

55341

Bravo

AF:

0.488

TwinsUK

AF:

0.332

AC:

1232

ALSPAC

AF:

0.316

AC:

1219

ESP6500AA

AF:

0.659

AC:

2895

ESP6500EA

AF:

0.314

AC:

2702

ExAC

AF:

0.467

AC:

56751

Asia WGS

AF:

0.781

AC:

2713

AN:

3478

EpiCase

AF:

0.309

EpiControl

AF:

0.302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Uncertain:1Benign:5

Jan 13, 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. -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: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

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 28, 2020

Leiden Open Variation Database

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Nikoletta Selenti. -

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23898106, 24728327, 27153395) -

Inborn genetic diseases

Benign:1

Oct 22, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Fanconi anemia

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.058

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.084

T;T

MetaRNN

Benign

0.0000014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;N

PhyloP100

0.077

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.030

N;N

REVEL

Benign

0.20

Sift

Benign

0.53

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.0

B;.

Vest4

0.045

ClinPred

0.00049

GERP RS

-0.17

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.022

gMVP

0.12

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.41

Position offset: -34

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

Publications

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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