chr2-174585532-C-T

Variant names:

• chr2-174585532-C-T
• rs111761533
• NM_001375834.1:c.42G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001375834.1(WIPF1):​c.42G>A​(p.Thr14Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,085,630 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (20 hom., cov: 28)
  • Exomes 𝑓: 0.0012 (10 hom.)
• Consequence: WIPF1 NM_001375834.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.16
• Publications: 1 publications found

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]

WIPF1 Gene-Disease associations (from GenCC):

• Wiskott-Aldrich syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Wiskott-Aldrich syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000236449 (HGNC:):

WIPF1-AS1 (HGNC:40613):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 2-174585532-C-T is Benign according to our data. Variant chr2-174585532-C-T is described in ClinVar as Benign. ClinVar VariationId is 472922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00905 (1181/130498) while in subpopulation AFR AF = 0.0321 (1131/35202). AF 95% confidence interval is 0.0306. There are 20 homozygotes in GnomAd4. There are 562 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375834.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WIPF1	NM_001375834.1	MANE Select	c.42G>A	p.Thr14Thr	synonymous	Exon 2 of 8	NP_001362763.1	A0A140VJZ9
	WIPF1	NM_001375835.1		c.42G>A	p.Thr14Thr	synonymous	Exon 2 of 9	NP_001362764.1	O43516-3
	WIPF1	NM_001077269.1		c.42G>A	p.Thr14Thr	synonymous	Exon 2 of 8	NP_001070737.1	Q2YDC4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WIPF1	ENST00000679041.1	MANE Select	c.42G>A	p.Thr14Thr	synonymous	Exon 2 of 8	ENSP00000503603.1	O43516-1
	WIPF1	ENST00000272746.9	TSL:1	c.42G>A	p.Thr14Thr	synonymous	Exon 2 of 9	ENSP00000272746.5	O43516-3
	WIPF1	ENST00000359761.7	TSL:1	c.42G>A	p.Thr14Thr	synonymous	Exon 2 of 8	ENSP00000352802.3	O43516-1

Frequencies

GnomAD3 genomes AF: 0.00905 AC: 1181 AN: 130440 Hom.: 20 Cov.: 28

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00232

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000557

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000794

Gnomad OTH AF: 0.00837

GnomAD2 exomes AF: 0.00215 AC: 525 AN: 244346 AF XY: 0.00151

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000450

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00119 AC: 1140 AN: 955132 Hom.: 10 Cov.: 39 AF XY: 0.00101 AC XY: 486 AN XY: 483122

African (AFR) AF: 0.0421 AC: 920 AN: 21874

American (AMR) AF: 0.00188 AC: 67 AN: 35604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15906

East Asian (EAS) AF: 0.00 AC: 0 AN: 16776

South Asian (SAS) AF: 0.000116 AC: 9 AN: 77594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33006

Middle Eastern (MID) AF: 0.00100 AC: 4 AN: 3988

European-Non Finnish (NFE) AF: 0.0000518 AC: 37 AN: 714282

Other (OTH) AF: 0.00285 AC: 103 AN: 36102

GnomAD4 genome AF: 0.00905 AC: 1181 AN: 130498 Hom.: 20 Cov.: 28 AF XY: 0.00904 AC XY: 562 AN XY: 62148

African (AFR) AF: 0.0321 AC: 1131 AN: 35202

American (AMR) AF: 0.00232 AC: 28 AN: 12074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3268

East Asian (EAS) AF: 0.00 AC: 0 AN: 3744

South Asian (SAS) AF: 0.000557 AC: 2 AN: 3590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.0000794 AC: 5 AN: 62940

Other (OTH) AF: 0.00830 AC: 15 AN: 1808

Alfa AF: 0.00333 Hom.: 5

Bravo AF: 0.00950

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	WIPF1-related disorder (1)
-	-	1	Wiskott-Aldrich syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.4
DANN	Benign	0.86
PhyloP100		-1.2
PromoterAI		-0.057	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs111761533; hg19: chr2-175450260;