2-174567080-G-A

Position:

• chr2-174567080-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001375834.1(WIPF1):​c.1446C>T​(p.Asn482=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,614,080 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (49 hom.)
• Consequence: WIPF1 NM_001375834.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0170

Genes affected

WIPF1 (HGNC:12736): (WAS/WASL interacting protein family member 1) This gene encodes a protein that plays an important role in the organization of the actin cytoskeleton. The encoded protein binds to a region of Wiskott-Aldrich syndrome protein that is frequently mutated in Wiskott-Aldrich syndrome, an X-linked recessive disorder. Impairment of the interaction between these two proteins may contribute to the disease. Two transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-174567080-G-A is Benign according to our data. Variant chr2-174567080-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 403609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.017 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00945 (1439/152288) while in subpopulation AFR AF= 0.018 (748/41546). AF 95% confidence interval is 0.0169. There are 7 homozygotes in gnomad4. There are 641 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WIPF1	NM_001375834.1	c.1446C>T	p.Asn482=	synonymous_variant	7/8	ENST00000679041.1	NP_001362763.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WIPF1	ENST00000679041.1	c.1446C>T	p.Asn482=	synonymous_variant	7/8		NM_001375834.1	ENSP00000503603	P3
	ENST00000442996.1	n.217+19603G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00945 AC: 1438 AN: 152170 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00655

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00544 AC: 1369 AN: 251458 Hom.: 10 AF XY: 0.00498 AC XY: 677 AN XY: 135908

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00582

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00632 AC: 9245 AN: 1461792 Hom.: 49 Cov.: 31 AF XY: 0.00613 AC XY: 4460 AN XY: 727198

Gnomad4 AFR exome AF: 0.0191

Gnomad4 AMR exome AF: 0.00572

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00676

Gnomad4 OTH exome AF: 0.00705

GnomAD4 genome AF: 0.00945 AC: 1439 AN: 152288 Hom.: 7 Cov.: 33 AF XY: 0.00861 AC XY: 641 AN XY: 74472

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.0132

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00656

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00820 Hom.: 4

Bravo AF: 0.0106

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00688

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, silent variant not in splice consensus -

Wiskott-Aldrich syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.5
DANN	Benign	0.91

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

Other links and lift over

dbSNP: rs116757787; hg19: chr2-175431808;