rs1800358

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000135.4(FANCA):c.3654A>G(p.Pro1218=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,613,748 control chromosomes in the GnomAD database, including 9,353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1498 hom., cov: 32)

Exomes 𝑓: 0.098 ( 7855 hom. )

Consequence

FANCA
NM_000135.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.82

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 16-89742911-T-C is Benign according to our data. Variant chr16-89742911-T-C is described in ClinVar as [Benign]. Clinvar id is 255261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.82 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 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.3654A>G	p.Pro1218=	synonymous_variant	37/43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3 linkuse as main transcript	c.3654A>G	p.Pro1218=	synonymous_variant	37/43		NP_001273096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.3654A>G	p.Pro1218=	synonymous_variant	37/43	1	NM_000135.4	ENSP00000373952	P1	O15360-1

Frequencies

GnomAD3 genomes

AF:

0.127

AC:

19285

AN:

152034

Hom.:

1494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.210

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0634

Gnomad ASJ

AF:

0.0857

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.122

Gnomad FIN

AF:

0.0849

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0944

Gnomad OTH

AF:

0.108

GnomAD3 exomes

AF:

0.101

AC:

25429

AN:

251310

Hom.:

1761

AF XY:

0.0999

AC XY:

13577

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.213

Gnomad AMR exome

AF:

0.0349

Gnomad ASJ exome

AF:

0.0819

Gnomad EAS exome

AF:

0.235

Gnomad SAS exome

AF:

0.107

Gnomad FIN exome

AF:

0.0841

Gnomad NFE exome

AF:

0.0882

Gnomad OTH exome

AF:

0.0822

GnomAD4 exome

AF:

0.0982

AC:

143511

AN:

1461596

Hom.:

7855

Cov.:

AF XY:

0.0982

AC XY:

71378

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.216

Gnomad4 AMR exome

AF:

0.0386

Gnomad4 ASJ exome

AF:

0.0810

Gnomad4 EAS exome

AF:

0.165

Gnomad4 SAS exome

AF:

0.106

Gnomad4 FIN exome

AF:

0.0806

Gnomad4 NFE exome

AF:

0.0947

Gnomad4 OTH exome

AF:

0.111

GnomAD4 genome

AF:

0.127

AC:

19312

AN:

152152

Hom.:

1498

Cov.:

AF XY:

0.124

AC XY:

9249

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.210

Gnomad4 AMR

AF:

0.0632

Gnomad4 ASJ

AF:

0.0857

Gnomad4 EAS

AF:

0.223

Gnomad4 SAS

AF:

0.122

Gnomad4 FIN

AF:

0.0849

Gnomad4 NFE

AF:

0.0943

Gnomad4 OTH

AF:

0.107

Alfa

AF:

0.103

Hom.:

497

Bravo

AF:

0.128

Asia WGS

AF:

0.177

AC:

614

AN:

3478

EpiCase

AF:

0.0899

EpiControl

AF:

0.0879

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Benign:4

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

not specified

Benign:2

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	- -

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

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.016

DANN

Benign

0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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