16-89816599-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000135.4(FANCA):c.17T>A(p.Val6Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0916 in 1,525,768 control chromosomes in the GnomAD database, including 7,080 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V6F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.065 ( 381 hom., cov: 34)

Exomes 𝑓: 0.095 ( 6699 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -0.160

Publications

29 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015743673).

BP6

Variant 16-89816599-A-T is Benign according to our data. Variant chr16-89816599-A-T is described in ClinVar as Benign. ClinVar VariationId is 134237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
FANCA	NM_000135.4 link	c.17T>A	p.Val6Asp	missense_variant	Exon 1 of 43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3 link	c.17T>A	p.Val6Asp	missense_variant	Exon 1 of 43		NP_001273096.1
FANCA	NM_001018112.3 link	c.17T>A	p.Val6Asp	missense_variant	Exon 1 of 11		NP_001018122.1
FANCA	NM_001351830.2 link	c.17T>A	p.Val6Asp	missense_variant	Exon 1 of 10		NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.17T>A	p.Val6Asp	missense_variant	Exon 1 of 43	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes

AF:

0.0650

AC:

9882

AN:

151928

Hom.:

381

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0180

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.0497

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.00444

Gnomad SAS

AF:

0.0807

Gnomad FIN

AF:

0.0723

Gnomad MID

AF:

0.0828

Gnomad NFE

AF:

0.0962

Gnomad OTH

AF:

0.0621

GnomAD2 exomes

AF:

0.0766

AC:

9382

AN:

122424

AF XY:

0.0799

show subpopulations

Gnomad AFR exome

AF:

0.0143

Gnomad AMR exome

AF:

0.0503

Gnomad ASJ exome

AF:

0.116

Gnomad EAS exome

AF:

0.00364

Gnomad FIN exome

AF:

0.0825

Gnomad NFE exome

AF:

0.0946

Gnomad OTH exome

AF:

0.0708

GnomAD4 exome

AF:

0.0945

AC:

129860

AN:

1373732

Hom.:

6699

Cov.:

AF XY:

0.0946

AC XY:

64190

AN XY:

678812

show subpopulations

African (AFR)

AF:

0.0144

AC:

419

AN:

29182

American (AMR)

AF:

0.0527

AC:

1874

AN:

35554

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

2819

AN:

24712

East Asian (EAS)

AF:

0.00160

AC:

AN:

34284

South Asian (SAS)

AF:

0.0907

AC:

7089

AN:

78120

European-Finnish (FIN)

AF:

0.0818

AC:

2755

AN:

33670

Middle Eastern (MID)

AF:

0.0975

AC:

427

AN:

4378

European-Non Finnish (NFE)

AF:

0.102

AC:

109652

AN:

1076550

Other (OTH)

AF:

0.0833

AC:

4770

AN:

57282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

6104

12208

18313

24417

30521

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4102

8204

12306

16408

20510

<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:

0.0650

AC:

9884

AN:

152036

Hom.:

381

Cov.:

AF XY:

0.0636

AC XY:

4729

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0180

AC:

745

AN:

41496

American (AMR)

AF:

0.0500

AC:

764

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

412

AN:

3466

East Asian (EAS)

AF:

0.00446

AC:

AN:

5160

South Asian (SAS)

AF:

0.0803

AC:

387

AN:

4818

European-Finnish (FIN)

AF:

0.0723

AC:

764

AN:

10570

Middle Eastern (MID)

AF:

0.0822

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0962

AC:

6534

AN:

67920

Other (OTH)

AF:

0.0620

AC:

131

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

485

970

1454

1939

2424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<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:

0.0855

Hom.:

117

Bravo

AF:

0.0600

TwinsUK

AF:

0.108

AC:

402

ALSPAC

AF:

0.107

AC:

411

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.0664

AC:

472

ExAC

AF:

0.0420

AC:

3989

Asia WGS

AF:

0.0540

AC:

185

AN:

3462

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Benign:4

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 11, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1Other:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

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

0.096

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.076

T;.;.;T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.54

T;T;T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;N;.;.;.

PhyloP100

-0.16

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.45

N;N;N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.043

D;D;T;T;T;T

Sift4G

Benign

0.062

T;D;D;D;D;D

Polyphen

0.072

B;.;.;.;B;B

Vest4

0.17

ClinPred

0.014

GERP RS

-2.1

PromoterAI

-0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.080

gMVP

0.30

Mutation Taster

=100/0

polymorphism (auto)

(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

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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