rs11648881

Variant summary

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

The NM_000135.4(FANCA):c.894-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0791 in 1,610,696 control chromosomes in the GnomAD database, including 6,090 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.062 ( 469 hom., cov: 33)

Exomes 𝑓: 0.081 ( 5621 hom. )

Consequence

FANCA
NM_000135.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001054

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.08

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 (BayesDel_noAF=-0.95).

BP6

Variant 16-89796026-T-C is Benign according to our data. Variant chr16-89796026-T-C is described in ClinVar as [Benign]. Clinvar id is 255270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4 linkuse as main transcript	c.894-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000389301.8
FANCA	NM_001286167.3 linkuse as main transcript	c.894-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.894-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000135.4	P1	O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0621

AC:

9442

AN:

152118

Hom.:

467

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.0392

Gnomad ASJ

AF:

0.0590

Gnomad EAS

AF:

0.240

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.0775

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0838

Gnomad OTH

AF:

0.0574

GnomAD3 exomes

AF:

0.0737

AC:

18515

AN:

251154

Hom.:

1172

AF XY:

0.0719

AC XY:

9758

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.0144

Gnomad AMR exome

AF:

0.0428

Gnomad ASJ exome

AF:

0.0598

Gnomad EAS exome

AF:

0.256

Gnomad SAS exome

AF:

0.0216

Gnomad FIN exome

AF:

0.0746

Gnomad NFE exome

AF:

0.0778

Gnomad OTH exome

AF:

0.0636

GnomAD4 exome

AF:

0.0808

AC:

117915

AN:

1458460

Hom.:

5621

Cov.:

AF XY:

0.0792

AC XY:

57450

AN XY:

725772

show subpopulations

Gnomad4 AFR exome

AF:

0.0116

Gnomad4 AMR exome

AF:

0.0404

Gnomad4 ASJ exome

AF:

0.0590

Gnomad4 EAS exome

AF:

0.171

Gnomad4 SAS exome

AF:

0.0227

Gnomad4 FIN exome

AF:

0.0725

Gnomad4 NFE exome

AF:

0.0869

Gnomad4 OTH exome

AF:

0.0853

GnomAD4 genome

AF:

0.0621

AC:

9447

AN:

152236

Hom.:

469

Cov.:

AF XY:

0.0605

AC XY:

4500

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0145

Gnomad4 AMR

AF:

0.0390

Gnomad4 ASJ

AF:

0.0590

Gnomad4 EAS

AF:

0.241

Gnomad4 SAS

AF:

0.0280

Gnomad4 FIN

AF:

0.0775

Gnomad4 NFE

AF:

0.0838

Gnomad4 OTH

AF:

0.0577

Alfa

AF:

0.0659

Hom.:

177

Bravo

AF:

0.0595

Asia WGS

AF:

0.119

AC:

412

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

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, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 02, 2019

This variant is associated with the following publications: (PMID: 23021409) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

Cadd

Benign

0.085

Dann

Benign

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000011

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.010

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