2-174562602-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001375834.1(WIPF1):c.1457G>A(p.Ser486Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: WIPF1 NM_001375834.1 missense, splice_region
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WIPF1	NM_001375834.1	c.1457G>A	p.Ser486Asn	missense_variant, splice_region_variant	8/8	ENST00000679041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WIPF1	ENST00000679041.1	c.1457G>A	p.Ser486Asn	missense_variant, splice_region_variant	8/8		NM_001375834.1	P3
	ENST00000442996.1	n.217+15125C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Wiskott-Aldrich syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 486 of the WIPF1 protein (p.Ser486Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with WIPF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2152752). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.69	N;N;N;N
REVEL	Benign	0.068
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.98	D;D;D;D
Vest4		0.18
MutPred		0.17		Loss of phosphorylation at S486 (P = 0.0055);Loss of phosphorylation at S486 (P = 0.0055);Loss of phosphorylation at S486 (P = 0.0055);Loss of phosphorylation at S486 (P = 0.0055);
MVP		0.28
MPC		0.93
ClinPred		0.84	D
GERP RS		4.9
Varity_R		0.21
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1684515884; hg19: chr2-175427330;