rs149531696

Positions:

chr16-89738637-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000135.4(FANCA):c.4332T>G(p.Pro1444=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000728 in 1,613,620 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00073 ( 5 hom. )

Consequence

FANCA
NM_000135.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.06

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:

ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

ZNF276 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=-0.9).

BP6

Variant 16-89738637-A-C is Benign according to our data. Variant chr16-89738637-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 255268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89738637-A-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-3.06 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000725 (1060/1461312) while in subpopulation MID AF= 0.00413 (23/5574). AF 95% confidence interval is 0.00282. There are 5 homozygotes in gnomad4_exome. There are 555 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4 linkuse as main transcript	c.4332T>G	p.Pro1444=	synonymous_variant	43/43	ENST00000389301.8	NP_000126.2
ZNF276	NM_001113525.2 linkuse as main transcript	c.*391A>C		3_prime_UTR_variant	11/11	ENST00000443381.7	NP_001106997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.4332T>G	p.Pro1444=	synonymous_variant	43/43	1	NM_000135.4	ENSP00000373952	P1	O15360-1
ZNF276	ENST00000443381.7 linkuse as main transcript	c.*391A>C		3_prime_UTR_variant	11/11	1	NM_001113525.2	ENSP00000415836	P2	Q8N554-1

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00112

AC:

277

AN:

248102

Hom.:

AF XY:

0.00122

AC XY:

164

AN XY:

134518

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.000725

AC:

1060

AN:

1461312

Hom.:

Cov.:

AF XY:

0.000763

AC XY:

555

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.0108

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000731

Gnomad4 FIN exome

AF:

0.0000941

Gnomad4 NFE exome

AF:

0.000496

Gnomad4 OTH exome

AF:

0.00172

GnomAD4 genome

AF:

0.000748

AC:

114

AN:

152308

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00145

Hom.:

Bravo

AF:

0.000740

EpiCase

AF:

0.00125

EpiControl

AF:

0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FANCA: BP4, BP7 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Fanconi anemia complementation group A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 30, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.057

DANN

Benign

0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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