rs1131660

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000135.4(FANCA):c.2151G>T(p.Met717Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,614,080 control chromosomes in the GnomAD database, including 750 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 61 hom., cov: 32)

Exomes 𝑓: 0.028 ( 689 hom. )

Consequence

FANCA
NM_000135.4 missense, splice_region

Scores

Splicing: ADA: 0.9958

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 1.27

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 -16 ACMG points.

BP6

Variant 16-89771678-C-A is Benign according to our data. Variant chr16-89771678-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 134252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89771678-C-A is described in Lovd as [Benign]. Variant chr16-89771678-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0221 (3371/152236) while in subpopulation AMR AF= 0.0371 (566/15276). AF 95% confidence interval is 0.0345. There are 61 homozygotes in gnomad4. There are 1599 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 61 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4 linkuse as main transcript	c.2151G>T	p.Met717Ile	missense_variant, splice_region_variant	23/43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3 linkuse as main transcript	c.2151G>T	p.Met717Ile	missense_variant, splice_region_variant	23/43		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.2151G>T	p.Met717Ile	missense_variant, splice_region_variant	23/43	1	NM_000135.4	ENSP00000373952	P1	O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0222

AC:

3374

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00678

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0371

Gnomad ASJ

AF:

0.0211

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.0125

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0322

Gnomad OTH

AF:

0.0340

GnomAD3 exomes

AF:

0.0220

AC:

5544

AN:

251478

Hom.:

AF XY:

0.0221

AC XY:

3001

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00566

Gnomad AMR exome

AF:

0.0225

Gnomad ASJ exome

AF:

0.0273

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00385

Gnomad FIN exome

AF:

0.0120

Gnomad NFE exome

AF:

0.0336

Gnomad OTH exome

AF:

0.0316

GnomAD4 exome

AF:

0.0281

AC:

41129

AN:

1461844

Hom.:

689

Cov.:

AF XY:

0.0275

AC XY:

20010

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00505

Gnomad4 AMR exome

AF:

0.0256

Gnomad4 ASJ exome

AF:

0.0275

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00444

Gnomad4 FIN exome

AF:

0.0126

Gnomad4 NFE exome

AF:

0.0324

Gnomad4 OTH exome

AF:

0.0292

GnomAD4 genome

AF:

0.0221

AC:

3371

AN:

152236

Hom.:

Cov.:

AF XY:

0.0215

AC XY:

1599

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00676

Gnomad4 AMR

AF:

0.0371

Gnomad4 ASJ

AF:

0.0211

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.0125

Gnomad4 NFE

AF:

0.0321

Gnomad4 OTH

AF:

0.0336

Alfa

AF:

0.0296

Hom.:

125

Bravo

AF:

0.0245

TwinsUK

AF:

0.0278

AC:

103

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.00546

AC:

ESP6500EA

AF:

0.0309

AC:

266

ExAC

AF:

0.0222

AC:

2694

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0368

EpiControl

AF:

0.0395

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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. -
Likely benign, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Sue Richards. -

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 02, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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

0.18

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Benign

0.81

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.27

T;T

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.28

Sift

Benign

0.18

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.0020

B;.

Vest4

0.071

MutPred

0.12

Gain of catalytic residue at L722 (P = 0.0711);Gain of catalytic residue at L722 (P = 0.0711);

ClinPred

0.0067

GERP RS

3.5

Varity_R

0.10

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.38

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.41

Position offset: -6

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