Genetic Variant WIPF3:p.Pro184Leu (chr7-29884045-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001080529.3(WIPF3):c.551C>T(p.Pro184Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000612 in 1,426,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 21)

Exomes 𝑓: 0.00065 ( 0 hom. )

Consequence

WIPF3
NM_001080529.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34

Variant links:

Genes affected

WIPF3 (HGNC:22004): (WAS/WASL interacting protein family member 3) Predicted to enable SH3 domain binding activity and actin binding activity. Predicted to be involved in actin filament-based movement. Predicted to be located in cytosol. Predicted to be active in actin filament. [provided by Alliance of Genome Resources, Apr 2022]

WIPF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.037021667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WIPF3	NM_001080529.3 link	c.551C>T	p.Pro184Leu	missense_variant	Exon 5 of 9	ENST00000242140.10	NP_001073998.2	A6NGB9
WIPF3	NM_001391973.1 link	c.551C>T	p.Pro184Leu	missense_variant	Exon 5 of 8		NP_001378902.1
WIPF3	XM_017012522.2 link	c.518C>T	p.Pro173Leu	missense_variant	Exon 4 of 8		XP_016868011.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WIPF3	ENST00000242140.10 link	c.551C>T	p.Pro184Leu	missense_variant	Exon 5 of 9	5	NM_001080529.3	ENSP00000242140.6		A6NGB9
WIPF3	ENST00000409123.5 link	c.551C>T	p.Pro184Leu	missense_variant	Exon 5 of 8	5		ENSP00000386790.1		A0A0A0MSG0

Frequencies

GnomAD3 genomes

AF:

0.000312

AC:

AN:

144008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000274

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000986

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000492

Gnomad OTH

AF:

0.00102

GnomAD3 exomes

AF:

0.000300

AC:

AN:

93440

Hom.:

AF XY:

0.000227

AC XY:

AN XY:

48378

show subpopulations

Gnomad AFR exome

AF:

0.000197

Gnomad AMR exome

AF:

0.000155

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000786

Gnomad OTH exome

AF:

0.000365

GnomAD4 exome

AF:

0.000646

AC:

828

AN:

1282022

Hom.:

Cov.:

AF XY:

0.000662

AC XY:

414

AN XY:

625564

show subpopulations

Gnomad4 AFR exome

AF:

0.000106

Gnomad4 AMR exome

AF:

0.000137

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000907

Gnomad4 NFE exome

AF:

0.000794

Gnomad4 OTH exome

AF:

0.000376

GnomAD4 genome

AF:

0.000312

AC:

AN:

144106

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

AN XY:

70126

show subpopulations

Gnomad4 AFR

AF:

0.000154

Gnomad4 AMR

AF:

0.000273

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000986

Gnomad4 NFE

AF:

0.000492

Gnomad4 OTH

AF:

0.00101

Alfa

AF:

0.0000693

Hom.:

ExAC

AF:

0.000200

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.551C>T (p.P184L) alteration is located in exon 5 (coding exon 4) of the WIPF3 gene. This alteration results from a C to T substitution at nucleotide position 551, causing the proline (P) at amino acid position 184 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Uncertain

0.47

.;T;T

Eigen

Benign

0.00011

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.58

T;T;.

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.037

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.3

.;M;M

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Benign

0.17

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.24

MVP

0.36

MPC

0.41

ClinPred

0.064

GERP RS

2.4

Varity_R

0.098

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over