16-89783072-C-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.1501G>A(p.Gly501Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,612,484 control chromosomes in the GnomAD database, including 164,130 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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. G501D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.51 ( 21693 hom., cov: 31)

Exomes 𝑓: 0.43 ( 142437 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:12O:1

Conservation

PhyloP100: -0.965

Publications

86 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=1.1434437E-6).

BP6

Variant 16-89783072-C-T is Benign according to our data. Variant chr16-89783072-C-T is described in ClinVar as Benign. ClinVar VariationId is 134244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.1501G>A	p.Gly501Ser	missense_variant	Exon 16 of 43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.1501G>A	p.Gly501Ser	missense_variant	Exon 16 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.1501G>A	p.Gly501Ser	missense_variant	Exon 16 of 43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.513

AC:

77894

AN:

151732

Hom.:

21654

Cov.:

show subpopulations

Gnomad AFR

AF:

0.684

Gnomad AMI

AF:

0.251

Gnomad AMR

AF:

0.525

Gnomad ASJ

AF:

0.329

Gnomad EAS

AF:

0.846

Gnomad SAS

AF:

0.511

Gnomad FIN

AF:

0.566

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.388

Gnomad OTH

AF:

0.463

GnomAD2 exomes

AF:

0.502

AC:

126084

AN:

251152

AF XY:

0.489

show subpopulations

Gnomad AFR exome

AF:

0.692

Gnomad AMR exome

AF:

0.621

Gnomad ASJ exome

AF:

0.337

Gnomad EAS exome

AF:

0.856

Gnomad FIN exome

AF:

0.560

Gnomad NFE exome

AF:

0.391

Gnomad OTH exome

AF:

0.443

GnomAD4 exome

AF:

0.428

AC:

625737

AN:

1460634

Hom.:

142437

Cov.:

AF XY:

0.429

AC XY:

311440

AN XY:

726668

show subpopulations

African (AFR)

AF:

0.696

AC:

23280

AN:

33454

American (AMR)

AF:

0.611

AC:

27321

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.338

AC:

8832

AN:

26126

East Asian (EAS)

AF:

0.845

AC:

33542

AN:

39696

South Asian (SAS)

AF:

0.501

AC:

43226

AN:

86224

European-Finnish (FIN)

AF:

0.546

AC:

29184

AN:

53408

Middle Eastern (MID)

AF:

0.467

AC:

2685

AN:

5750

European-Non Finnish (NFE)

AF:

0.388

AC:

430762

AN:

1110942

Other (OTH)

AF:

0.446

AC:

26905

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

19185

38369

57554

76738

95923

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13804

27608

41412

55216

69020

<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:

0.514

AC:

77995

AN:

151850

Hom.:

21693

Cov.:

AF XY:

0.523

AC XY:

38780

AN XY:

74198

show subpopulations

African (AFR)

AF:

0.685

AC:

28339

AN:

41390

American (AMR)

AF:

0.526

AC:

8028

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.329

AC:

1136

AN:

3458

East Asian (EAS)

AF:

0.846

AC:

4360

AN:

5154

South Asian (SAS)

AF:

0.509

AC:

2447

AN:

4806

European-Finnish (FIN)

AF:

0.566

AC:

5962

AN:

10538

Middle Eastern (MID)

AF:

0.435

AC:

128

AN:

294

European-Non Finnish (NFE)

AF:

0.388

AC:

26386

AN:

67938

Other (OTH)

AF:

0.465

AC:

981

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1775

3549

5324

7098

8873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

672

1344

2016

2688

3360

<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:

0.426

Hom.:

49053

Bravo

AF:

0.521

TwinsUK

AF:

0.398

AC:

1477

ALSPAC

AF:

0.370

AC:

1427

ESP6500AA

AF:

0.680

AC:

2991

ESP6500EA

AF:

0.381

AC:

3277

ExAC

AF:

0.499

AC:

60629

Asia WGS

AF:

0.658

AC:

2288

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Uncertain:1Benign:6

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 19, 2022

Fulgent Genetics, Fulgent Genetics

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 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

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. -

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. -

not specified

Benign:3Other:1

Dec 03, 2021

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

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

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: 27153395, 23021409, 24286411, 24728327) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.058

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.29

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.058

T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.024

T;T

MetaRNN

Benign

0.0000011

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.2

N;N

PhyloP100

-0.96

PrimateAI

Benign

0.27

PROVEAN

Benign

1.5

N;N

REVEL

Benign

0.26

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.024

ClinPred

0.0014

GERP RS

-4.6

Varity_R

0.022

gMVP

0.23

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