2-174567091-G-C

Variant names:

• chr2-174567091-G-C
• rs1274242254
• NM_001375834.1:c.1435C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001375834.1(WIPF1):​c.1435C>G​(p.Leu479Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WIPF1 NM_001375834.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.999
• Publications: 0 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:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034019798).

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.1435C>G	p.Leu479Val	missense	Exon 7 of 8	NP_001362763.1	A0A140VJZ9
	WIPF1	NM_001375835.1		c.1435C>G	p.Leu479Val	missense	Exon 7 of 9	NP_001362764.1	O43516-3
	WIPF1	NM_001077269.1		c.1435C>G	p.Leu479Val	missense	Exon 7 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.1435C>G	p.Leu479Val	missense	Exon 7 of 8	ENSP00000503603.1	O43516-1
	WIPF1	ENST00000272746.9	TSL:1	c.1435C>G	p.Leu479Val	missense	Exon 7 of 9	ENSP00000272746.5	O43516-3
	WIPF1	ENST00000359761.7	TSL:1	c.1435C>G	p.Leu479Val	missense	Exon 7 of 8	ENSP00000352802.3	O43516-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Wiskott-Aldrich syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.17
DANN	Benign	0.94
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.3	L
PhyloP100		-1.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.15
Sift	Benign	0.066	T
Sift4G	Benign	0.58	T
Polyphen		0.0040	B
Vest4		0.12
MutPred		0.13		Gain of MoRF binding (P = 0.0923)
MVP		0.19
MPC		0.33
ClinPred		0.18	T
GERP RS		-12
Varity_R		0.034
gMVP		0.093
Mutation Taster		=88/12	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: rs1274242254; hg19: chr2-175431819;