3-149657083-C-A

Position:

• chr3-149657083-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.398

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 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	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	c.224G>T	p.Gly75Val	missense_variant	2/7	1	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

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

Not reported in ClinVar

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
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

Other links and lift over

dbSNP: rs1713282358; hg19: chr3-149374870;