16-89791527-G-A

Position:

chr16-89791527-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_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 (★★).

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:9O:1

Conservation

PhyloP100: 4.09

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:

FANCA (HGNC:):

FANCA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 16-89791527-G-A is Benign according to our data. Variant chr16-89791527-G-A is described in ClinVar as [Likely_benign]. Clinvar id 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/exons	MANE	Protein	UniProt
FANCA	NM_000135.4 linkuse as main transcript	c.1235C>T	p.Ala412Val	missense_variant	14/43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 linkuse as main transcript	c.1235C>T	p.Ala412Val	missense_variant	14/43		NP_001273096.1	O15360-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.1235C>T	p.Ala412Val	missense_variant	14/43	1	NM_000135.4	ENSP00000373952.3		O15360-1

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

GnomAD3 exomes

AF:

0.0663

AC:

16631

AN:

250772

Hom.:

971

AF XY:

0.0654

AC XY:

8872

AN XY:

135594

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 SAS exome

AF:

0.0210

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

Gnomad4 AFR exome

AF:

0.0113

Gnomad4 AMR exome

AF:

0.0203

Gnomad4 ASJ exome

AF:

0.0570

Gnomad4 EAS exome

AF:

0.157

Gnomad4 SAS exome

AF:

0.0220

Gnomad4 FIN exome

AF:

0.0573

Gnomad4 NFE exome

AF:

0.0865

Gnomad4 OTH exome

AF:

0.0824

GnomAD4 genome

AF:

0.0592

AC:

9007

AN:

152222

Hom.:

413

Cov.:

AF XY:

0.0570

AC XY:

4240

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0139

Gnomad4 AMR

AF:

0.0348

Gnomad4 ASJ

AF:

0.0577

Gnomad4 EAS

AF:

0.216

Gnomad4 SAS

AF:

0.0265

Gnomad4 FIN

AF:

0.0613

Gnomad4 NFE

AF:

0.0832

Gnomad4 OTH

AF:

0.0549

Alfa

AF:

0.0769

Hom.:

1307

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:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2016	- -

Fanconi anemia complementation group A

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2019	This variant is associated with the following publications: (PMID: 27153395, 10094191, 23021409, 24286411, 27884173, 24728327) -
Likely 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

0.13

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

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

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

Polyphen

0.95

P;.

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

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

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