chr3-149657111-T-C

Position:

• chr3-149657111-T-C

Variant summary

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

The NM_015472.6(WWTR1):​c.196A>G​(p.Ser66Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WWTR1 NM_015472.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWTR1	NM_015472.6	c.196A>G	p.Ser66Gly	missense_variant	2/7	ENST00000360632.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWTR1	ENST00000360632.8	c.196A>G	p.Ser66Gly	missense_variant	2/7	1	NM_015472.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1431632 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 710014

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Apr 26, 2023

The c.196A>G (p.S66G) alteration is located in exon 2 (coding exon 1) of the WWTR1 gene. This alteration results from a A to G substitution at nucleotide position 196, causing the serine (S) at amino acid position 66 to be replaced by a glycine (G). 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	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D;D;.;.;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.7	M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D
REVEL	Benign	0.24
Sift	Benign	0.039	D;D;D;D;T;D
Sift4G	Benign	0.086	T;T;T;.;.;.
Polyphen		0.96	P;P;P;.;.;.
Vest4		0.51
MutPred		0.19		Loss of phosphorylation at S66 (P = 0.0035);Loss of phosphorylation at S66 (P = 0.0035);Loss of phosphorylation at S66 (P = 0.0035);Loss of phosphorylation at S66 (P = 0.0035);Loss of phosphorylation at S66 (P = 0.0035);Loss of phosphorylation at S66 (P = 0.0035);
MVP		0.34
MPC		1.3
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.41
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-149374898;