rs17232910

Positions:

chr16-89773358-G-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.1927C>G(p.Pro643Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.078 in 1,550,812 control chromosomes in the GnomAD database, including 5,683 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.060 ( 437 hom., cov: 32)

Exomes 𝑓: 0.080 ( 5246 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0740

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:

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=0.0039646924).

BP6

Variant 16-89773358-G-C is Benign according to our data. Variant chr16-89773358-G-C is described in ClinVar as [Benign]. Clinvar id is 134247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 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.1927C>G	p.Pro643Ala	missense_variant	22/43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3 linkuse as main transcript	c.1927C>G	p.Pro643Ala	missense_variant	22/43		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.1927C>G	p.Pro643Ala	missense_variant	22/43	1	NM_000135.4	ENSP00000373952	P1	O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0602

AC:

9162

AN:

152146

Hom.:

436

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0140

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0379

Gnomad ASJ

AF:

0.0591

Gnomad EAS

AF:

0.233

Gnomad SAS

AF:

0.0269

Gnomad FIN

AF:

0.0613

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0834

Gnomad OTH

AF:

0.0550

GnomAD3 exomes

AF:

0.0677

AC:

10573

AN:

156116

Hom.:

676

AF XY:

0.0674

AC XY:

5538

AN XY:

82116

show subpopulations

Gnomad AFR exome

AF:

0.0142

Gnomad AMR exome

AF:

0.0211

Gnomad ASJ exome

AF:

0.0571

Gnomad EAS exome

AF:

0.257

Gnomad SAS exome

AF:

0.0217

Gnomad FIN exome

AF:

0.0594

Gnomad NFE exome

AF:

0.0809

Gnomad OTH exome

AF:

0.0585

GnomAD4 exome

AF:

0.0800

AC:

111828

AN:

1398546

Hom.:

5246

Cov.:

AF XY:

0.0786

AC XY:

54209

AN XY:

689814

show subpopulations

Gnomad4 AFR exome

AF:

0.0111

Gnomad4 AMR exome

AF:

0.0227

Gnomad4 ASJ exome

AF:

0.0578

Gnomad4 EAS exome

AF:

0.163

Gnomad4 SAS exome

AF:

0.0225

Gnomad4 FIN exome

AF:

0.0569

Gnomad4 NFE exome

AF:

0.0870

Gnomad4 OTH exome

AF:

0.0839

GnomAD4 genome

AF:

0.0602

AC:

9169

AN:

152266

Hom.:

437

Cov.:

AF XY:

0.0582

AC XY:

4337

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0140

Gnomad4 AMR

AF:

0.0378

Gnomad4 ASJ

AF:

0.0591

Gnomad4 EAS

AF:

0.234

Gnomad4 SAS

AF:

0.0278

Gnomad4 FIN

AF:

0.0613

Gnomad4 NFE

AF:

0.0834

Gnomad4 OTH

AF:

0.0553

Alfa

AF:

0.0805

Hom.:

433

Bravo

AF:

0.0580

TwinsUK

AF:

0.0987

AC:

366

ALSPAC

AF:

0.0830

AC:

320

ESP6500AA

AF:

0.0125

AC:

ESP6500EA

AF:

0.0659

AC:

519

ExAC

AF:

0.0245

AC:

1457

Asia WGS

AF:

0.117

AC:

407

AN:

3478

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:3

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	- -
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. -

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2019	- -
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

0.072

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.76

DANN

Benign

0.37

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.41

T;T

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;L

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.5

N;N

REVEL

Benign

0.23

Sift

Benign

0.45

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0010

B;.

Vest4

0.032

ClinPred

0.0011

GERP RS

-2.4

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.019

gMVP

0.24

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

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