3-149657083-C-A

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

4
15

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

Genome browser will be placed here

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
WWTR1NM_015472.6 linkuse as main transcriptc.224G>T p.Gly75Val missense_variant 2/7 ENST00000360632.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WWTR1ENST00000360632.8 linkuse as main transcriptc.224G>T p.Gly75Val missense_variant 2/71 NM_015472.6 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000141
AC:
20
AN:
1417266
Hom.:
0
Cov.:
32
AF XY:
0.0000114
AC XY:
8
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.:
33
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 submitterclinical testingAmbry GeneticsMay 28, 2024The 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
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
22
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
D
LIST_S2
Benign
0.78
.;.;T;T;T;T
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.20
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;L;L;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.67
T
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
D
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.

Other links and lift over

dbSNP: rs1713282358; hg19: chr3-149374870; API