rs4972450

chr2-174572212-G-Achr2-174572212-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001375834.1(WIPF1):c.593C>T(p.Pro198Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.949 in 1,614,064 control chromosomes in the GnomAD database, including 727,748 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (65277 hom., cov: 31)
  • Exomes 𝑓: 0.95 (662471 hom.)
• Consequence: WIPF1 NM_001375834.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 2.50

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.5518626E-7).
• BP6: Variant 2-174572212-G-A is Benign according to our data. Variant chr2-174572212-G-A is described in ClinVar as [Benign]. Clinvar id is 403608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-174572212-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WIPF1	NM_001375834.1	c.593C>T	p.Pro198Leu	missense_variant	5/8	ENST00000679041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WIPF1	ENST00000679041.1	c.593C>T	p.Pro198Leu	missense_variant	5/8		NM_001375834.1	P3
	ENST00000442996.1	n.217+24735G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.925 AC: 140602 AN: 152064 Hom.: 65237 Cov.: 31

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.939

Gnomad AMR AF: 0.949

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.891

Gnomad FIN AF: 0.979

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.957

Gnomad OTH AF: 0.929

GnomAD3 exomes AF: 0.945 AC: 236375 AN: 250224 Hom.: 111887 AF XY: 0.943 AC XY: 127783 AN XY: 135548

Gnomad AFR exome AF: 0.839

Gnomad AMR exome AF: 0.968

Gnomad ASJ exome AF: 0.932

Gnomad EAS exome AF: 0.992

Gnomad SAS exome AF: 0.884

Gnomad FIN exome AF: 0.976

Gnomad NFE exome AF: 0.956

Gnomad OTH exome AF: 0.949

GnomAD4 exome AF: 0.952 AC: 1391054 AN: 1461882 Hom.: 662471 Cov.: 95 AF XY: 0.950 AC XY: 690676 AN XY: 727244

Gnomad4 AFR exome AF: 0.850

Gnomad4 AMR exome AF: 0.966

Gnomad4 ASJ exome AF: 0.927

Gnomad4 EAS exome AF: 0.989

Gnomad4 SAS exome AF: 0.888

Gnomad4 FIN exome AF: 0.975

Gnomad4 NFE exome AF: 0.958

Gnomad4 OTH exome AF: 0.942

GnomAD4 genome AF: 0.925 AC: 140702 AN: 152182 Hom.: 65277 Cov.: 31 AF XY: 0.926 AC XY: 68864 AN XY: 74402

Gnomad4 AFR AF: 0.843

Gnomad4 AMR AF: 0.950

Gnomad4 ASJ AF: 0.929

Gnomad4 EAS AF: 0.991

Gnomad4 SAS AF: 0.890

Gnomad4 FIN AF: 0.979

Gnomad4 NFE AF: 0.957

Gnomad4 OTH AF: 0.925

Alfa AF: 0.949 Hom.: 145700

Bravo AF: 0.922

TwinsUK AF: 0.962 AC: 3567

ALSPAC AF: 0.962 AC: 3707

ESP6500AA AF: 0.853 AC: 3757

ESP6500EA AF: 0.959 AC: 8242

ExAC AF: 0.941 AC: 114151

Asia WGS AF: 0.901 AC: 3132 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wiskott-Aldrich syndrome 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

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 -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied by a panel of primary immunodeficiencies. Number of patients: 88. Only high quality variants are reported. -

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	14
Dann	Benign	0.71
DEOGEN2	Benign	0.16	T;.;T;T;.;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.053	N
MetaRNN	Benign	5.6e-7	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.3	N;N;N;N;N;.
MutationTaster	Benign	0.91	P;P;P;P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.0	N;N;N;N;N;N
REVEL	Benign	0.063
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	0.55	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.050
MPC		0.33
ClinPred		0.0018	T
GERP RS		5.0
Varity_R		0.022
gMVP		0.11

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: rs4972450; hg19: chr2-175436940;