dbSNP rs1459922346: WWTR1:p.Gly99Arg (chr3-149657012-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015472.6(WWTR1):c.295G>C(p.Gly99Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,972 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G99S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

WWTR1
NM_015472.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.14

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13428938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWTR1	NM_015472.6 link	c.295G>C	p.Gly99Arg	missense_variant	Exon 2 of 7	ENST00000360632.8	NP_056287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWTR1	ENST00000360632.8 link	c.295G>C	p.Gly99Arg	missense_variant	Exon 2 of 7	1	NM_015472.6	ENSP00000353847.3		Q9GZV5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000467

AC:

AN:

214264

Hom.:

AF XY:

0.00

AC XY:

AN XY:

118998

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000308

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442972

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717570

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000230

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;T;T;.;.;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.81

.;.;T;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.13

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L;L;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.0

N;N;N;N;N;N

REVEL

Benign

0.029

Sift

Uncertain

0.029

D;D;D;T;T;D

Sift4G

Benign

0.60

T;T;T;.;.;.

Polyphen

0.0060

B;B;B;.;.;.

Vest4

0.15

MutPred

0.31

Gain of MoRF binding (P = 0.0075);Gain of MoRF binding (P = 0.0075);Gain of MoRF binding (P = 0.0075);Gain of MoRF binding (P = 0.0075);Gain of MoRF binding (P = 0.0075);Gain of MoRF binding (P = 0.0075);

MVP

0.093

MPC

1.0

ClinPred

0.65

GERP RS

4.2

Varity_R

0.076

gMVP

0.43

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over