rs9282681

Positions:

chr16-89739506-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000135.4(FANCA):c.3982A>G(p.Thr1328Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0777 in 1,551,258 control chromosomes in the GnomAD database, including 5,562 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 421 hom., cov: 33)

Exomes 𝑓: 0.080 ( 5141 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.994

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 links:

ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

ZNF276 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007843435).

BP6

Variant 16-89739506-T-C is Benign according to our data. Variant chr16-89739506-T-C is described in ClinVar as [Benign]. Clinvar id is 134278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89739506-T-C is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4 linkuse as main transcript	c.3982A>G	p.Thr1328Ala	missense_variant	40/43	ENST00000389301.8	NP_000126.2
ZNF276	NM_001113525.2 linkuse as main transcript	c.*1260T>C		3_prime_UTR_variant	11/11	ENST00000443381.7	NP_001106997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.3982A>G	p.Thr1328Ala	missense_variant	40/43	1	NM_000135.4	ENSP00000373952	P1	O15360-1
ZNF276	ENST00000443381.7 linkuse as main transcript	c.*1260T>C		3_prime_UTR_variant	11/11	1	NM_001113525.2	ENSP00000415836	P2	Q8N554-1

Frequencies

GnomAD3 genomes

AF:

0.0596

AC:

9071

AN:

152126

Hom.:

420

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0140

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0376

Gnomad ASJ

AF:

0.0580

Gnomad EAS

AF:

0.218

Gnomad SAS

AF:

0.0263

Gnomad FIN

AF:

0.0613

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0833

Gnomad OTH

AF:

0.0569

GnomAD3 exomes

AF:

0.0661

AC:

10322

AN:

156058

Hom.:

617

AF XY:

0.0661

AC XY:

5444

AN XY:

82302

show subpopulations

Gnomad AFR exome

AF:

0.0139

Gnomad AMR exome

AF:

0.0210

Gnomad ASJ exome

AF:

0.0563

Gnomad EAS exome

AF:

0.238

Gnomad SAS exome

AF:

0.0215

Gnomad FIN exome

AF:

0.0609

Gnomad NFE exome

AF:

0.0803

Gnomad OTH exome

AF:

0.0568

GnomAD4 exome

AF:

0.0797

AC:

111444

AN:

1399014

Hom.:

5141

Cov.:

AF XY:

0.0783

AC XY:

54032

AN XY:

690082

show subpopulations

Gnomad4 AFR exome

AF:

0.0112

Gnomad4 AMR exome

AF:

0.0226

Gnomad4 ASJ exome

AF:

0.0563

Gnomad4 EAS exome

AF:

0.153

Gnomad4 SAS exome

AF:

0.0222

Gnomad4 FIN exome

AF:

0.0579

Gnomad4 NFE exome

AF:

0.0870

Gnomad4 OTH exome

AF:

0.0831

GnomAD4 genome

AF:

0.0596

AC:

9078

AN:

152244

Hom.:

421

Cov.:

AF XY:

0.0575

AC XY:

4280

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0139

Gnomad4 AMR

AF:

0.0375

Gnomad4 ASJ

AF:

0.0580

Gnomad4 EAS

AF:

0.219

Gnomad4 SAS

AF:

0.0272

Gnomad4 FIN

AF:

0.0613

Gnomad4 NFE

AF:

0.0833

Gnomad4 OTH

AF:

0.0572

Alfa

AF:

0.0796

Hom.:

871

Bravo

AF:

0.0572

TwinsUK

AF:

0.0984

AC:

365

ALSPAC

AF:

0.0823

AC:

317

ESP6500AA

AF:

0.0136

AC:

ESP6500EA

AF:

0.0706

AC:

579

ExAC

AF:

0.0307

AC:

2659

Asia WGS

AF:

0.113

AC:

392

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2021	Variant summary: FANCA c.3982A>G (p.Thr1328Ala) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.066 in 156058 control chromosomes in the gnomAD database, including 617 homozygotes. The observed variant frequency is approximately 30.55 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia phenotype (0.0022), strongly suggesting that the variant is benign. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five classified the variant as benign while one classified as pathogenic. Based on the evidence outlined above, the variant was classified as benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2016	- -

Fanconi anemia complementation group A

Pathogenic:1Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Pathogenic, flagged submission	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2019	This variant is associated with the following publications: (PMID: 31586946, 9371798, 27121516) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.11

DANN

Benign

0.44

DEOGEN2

Benign

0.14

T;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.42

T;T;T

MetaRNN

Benign

0.0078

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.83

L;L;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.85

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.44

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.0050

B;.;.

Vest4

0.017

ClinPred

0.00030

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over