NM_001375834.1:c.593C>T

Variant names:

• chr2-174572212-G-A
• rs4972450
• NM_001375834.1:c.593C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P198Q) has been classified as Uncertain significance.

• 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:8 O:1
• Conservation: PhyloP100: 2.50
• Publications: 24 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: Benign. The variant received -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 VariationId is 403608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

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.593C>T	p.Pro198Leu	missense	Exon 5 of 8	NP_001362763.1	A0A140VJZ9
	WIPF1	NM_001375835.1		c.593C>T	p.Pro198Leu	missense	Exon 5 of 9	NP_001362764.1	O43516-3
	WIPF1	NM_001077269.1		c.593C>T	p.Pro198Leu	missense	Exon 5 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.593C>T	p.Pro198Leu	missense	Exon 5 of 8	ENSP00000503603.1	O43516-1
	WIPF1	ENST00000272746.9	TSL:1	c.593C>T	p.Pro198Leu	missense	Exon 5 of 9	ENSP00000272746.5	O43516-3
	WIPF1	ENST00000359761.7	TSL:1	c.593C>T	p.Pro198Leu	missense	Exon 5 of 8	ENSP00000352802.3	O43516-1

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

GnomAD2 exomes AF: 0.945 AC: 236375 AN: 250224 AF XY: 0.943

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 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

African (AFR) AF: 0.850 AC: 28452 AN: 33480

American (AMR) AF: 0.966 AC: 43216 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.927 AC: 24233 AN: 26136

East Asian (EAS) AF: 0.989 AC: 39267 AN: 39700

South Asian (SAS) AF: 0.888 AC: 76605 AN: 86258

European-Finnish (FIN) AF: 0.975 AC: 52097 AN: 53414

Middle Eastern (MID) AF: 0.907 AC: 5233 AN: 5768

European-Non Finnish (NFE) AF: 0.958 AC: 1065049 AN: 1112006

Other (OTH) AF: 0.942 AC: 56902 AN: 60396

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

African (AFR) AF: 0.843 AC: 34991 AN: 41492

American (AMR) AF: 0.950 AC: 14522 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.929 AC: 3226 AN: 3472

East Asian (EAS) AF: 0.991 AC: 5122 AN: 5168

South Asian (SAS) AF: 0.890 AC: 4289 AN: 4820

European-Finnish (FIN) AF: 0.979 AC: 10386 AN: 10610

Middle Eastern (MID) AF: 0.925 AC: 272 AN: 294

European-Non Finnish (NFE) AF: 0.957 AC: 65085 AN: 68008

Other (OTH) AF: 0.925 AC: 1953 AN: 2112

Alfa AF: 0.946 Hom.: 282287

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Wiskott-Aldrich syndrome 2 (3)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	5.6e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.3	N
PhyloP100		2.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.063
Sift	Benign	1.0	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.050
MPC		0.33
ClinPred		0.0018	T
GERP RS		5.0
Varity_R		0.022
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs4972450; hg19: chr2-175436940; COSMIC: COSV107247904; COSMIC: COSV107247904;