Variant chr3-149657083-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015472.6(WWTR1):c.224G>T(p.Gly75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,417,266 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

WWTR1
NM_015472.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.398

Variant links:

Genes affected

WWTR1 (HGNC:24042): (WW domain containing transcription regulator 1) Enables transcription coactivator activity. Involved in several processes, including hippo signaling; positive regulation of cell differentiation; and regulation of signal transduction. Located in cytosol and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

WWTR1 links:

WWTR1-AS1 (HGNC:41035): (WWTR1 antisense RNA 1)

WWTR1-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1970979).

BS2

High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWTR1	NM_015472.6 linkuse as main transcript	c.224G>T	p.Gly75Val	missense_variant	2/7	ENST00000360632.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWTR1	ENST00000360632.8 linkuse as main transcript	c.224G>T	p.Gly75Val	missense_variant	2/7	1	NM_015472.6	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000141

AC:

AN:

1417266

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

702040

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000156

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The c.224G>T (p.G75V) alteration is located in exon 2 (coding exon 1) of the WWTR1 gene. This alteration results from a G to T substitution at nucleotide position 224, causing the glycine (G) at amino acid position 75 to be replaced by a valine (V). 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

0.075

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T;T;.;.;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.78

.;.;T;T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.20

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.2

N;N;N;N;N;N

REVEL

Benign

0.098

Sift

Uncertain

0.020

D;D;D;D;T;T

Sift4G

Uncertain

0.032

D;D;D;.;.;.

Polyphen

0.91

P;P;P;.;.;.

Vest4

0.29

MutPred

0.26

Loss of catalytic residue at G75 (P = 0.0171);Loss of catalytic residue at G75 (P = 0.0171);Loss of catalytic residue at G75 (P = 0.0171);Loss of catalytic residue at G75 (P = 0.0171);Loss of catalytic residue at G75 (P = 0.0171);Loss of catalytic residue at G75 (P = 0.0171);

MVP

0.11

MPC

1.5

ClinPred

0.73

GERP RS

3.7

Varity_R

0.17

gMVP

0.36

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