chr3-149657285-G-T

Position:

• chr3-149657285-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015472.6(WWTR1):​c.22C>A​(p.Pro8Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: WWTR1 NM_015472.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.83

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)

ACMG classification

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=0.17842004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWTR1	NM_015472.6	c.22C>A	p.Pro8Thr	missense_variant	2/7	ENST00000360632.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWTR1	ENST00000360632.8	c.22C>A	p.Pro8Thr	missense_variant	2/7	1	NM_015472.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2023

The c.22C>A (p.P8T) alteration is located in exon 2 (coding exon 1) of the WWTR1 gene. This alteration results from a C to A substitution at nucleotide position 22, causing the proline (P) at amino acid position 8 to be replaced by a threonine (T). 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	0.056
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;T;.;.;T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.044
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.63	.;.;T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L;.;.;.;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;D
REVEL	Benign	0.068
Sift	Benign	0.26	T;T;T;T;T;T;.
Sift4G	Benign	0.11	T;T;T;.;.;.;.
Polyphen		0.0	B;B;B;.;.;.;.
Vest4		0.24
MutPred		0.43		Gain of phosphorylation at P8 (P = 0.0277);Gain of phosphorylation at P8 (P = 0.0277);Gain of phosphorylation at P8 (P = 0.0277);Gain of phosphorylation at P8 (P = 0.0277);Gain of phosphorylation at P8 (P = 0.0277);Gain of phosphorylation at P8 (P = 0.0277);Gain of phosphorylation at P8 (P = 0.0277);
MVP		0.13
MPC		1.1
ClinPred		0.77	D
GERP RS		3.6
Varity_R		0.17
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-149375072;