rs11646374

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1BP6_Very_StrongBA1

The NM_000135.4(FANCA):c.1235C>T(p.Ala412Val) variant causes a missense change. The variant allele was found at a frequency of 0.0769 in 1,613,900 control chromosomes in the GnomAD database, including 5,714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A412P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.059 ( 413 hom., cov: 32)

Exomes 𝑓: 0.079 ( 5301 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 4.09

Publications

41 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 -14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 23 uncertain in NM_000135.4

BP6

Variant 16-89791527-G-A is Benign according to our data. Variant chr16-89791527-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.1235C>T	p.Ala412Val	missense_variant	Exon 14 of 43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3 link	c.1235C>T	p.Ala412Val	missense_variant	Exon 14 of 43		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.1235C>T	p.Ala412Val	missense_variant	Exon 14 of 43	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes

AF:

0.0592

AC:

9001

AN:

152104

Hom.:

412

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0140

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0348

Gnomad ASJ

AF:

0.0577

Gnomad EAS

AF:

0.216

Gnomad SAS

AF:

0.0257

Gnomad FIN

AF:

0.0613

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0833

Gnomad OTH

AF:

0.0545

GnomAD2 exomes

AF:

0.0663

AC:

16631

AN:

250772

AF XY:

0.0654

show subpopulations

Gnomad AFR exome

AF:

0.0140

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.0588

Gnomad EAS exome

AF:

0.232

Gnomad FIN exome

AF:

0.0583

Gnomad NFE exome

AF:

0.0766

Gnomad OTH exome

AF:

0.0568

GnomAD4 exome

AF:

0.0788

AC:

115169

AN:

1461678

Hom.:

5301

Cov.:

AF XY:

0.0772

AC XY:

56160

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.0113

AC:

377

AN:

33478

American (AMR)

AF:

0.0203

AC:

909

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0570

AC:

1490

AN:

26134

East Asian (EAS)

AF:

0.157

AC:

6220

AN:

39690

South Asian (SAS)

AF:

0.0220

AC:

1898

AN:

86248

European-Finnish (FIN)

AF:

0.0573

AC:

3058

AN:

53332

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0865

AC:

96166

AN:

1111930

Other (OTH)

AF:

0.0824

AC:

4975

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

6482

12964

19445

25927

32409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3584

7168

10752

14336

17920

<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:

0.0592

AC:

9007

AN:

152222

Hom.:

413

Cov.:

AF XY:

0.0570

AC XY:

4240

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0139

AC:

579

AN:

41550

American (AMR)

AF:

0.0348

AC:

531

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0577

AC:

200

AN:

3466

East Asian (EAS)

AF:

0.216

AC:

1120

AN:

5174

South Asian (SAS)

AF:

0.0265

AC:

128

AN:

4822

European-Finnish (FIN)

AF:

0.0613

AC:

650

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0832

AC:

5661

AN:

68002

Other (OTH)

AF:

0.0549

AC:

116

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

423

846

1270

1693

2116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0748

Hom.:

1726

Bravo

AF:

0.0568

TwinsUK

AF:

0.0987

AC:

366

ALSPAC

AF:

0.0825

AC:

318

ESP6500AA

AF:

0.0173

AC:

ESP6500EA

AF:

0.0812

AC:

698

ExAC

AF:

0.0649

AC:

7878

Asia WGS

AF:

0.109

AC:

376

AN:

3478

EpiCase

AF:

0.0746

EpiControl

AF:

0.0721

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Benign:5

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

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.

Jul 10, 2025

GeneKor MSA

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

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance: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 12, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27153395, 10094191, 23021409, 24286411, 27884173, 24728327)

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

0.13

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M

PhyloP100

4.1

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.3

N;N

REVEL

Uncertain

0.35

Sift

Benign

0.089

T;T

Sift4G

Uncertain

0.034

D;D

Vest4

0.15

ClinPred

0.031

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.076

gMVP

0.15

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: -17

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