chr3-149527912-C-T

Variant names:

• chr3-149527912-C-T
• rs149464192
• NM_015472.6:c.829G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015472.6(WWTR1):​c.829G>A​(p.Ala277Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. A277P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WWTR1 NM_015472.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04793173).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015472.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWTR1	NM_015472.6	MANE Select	c.829G>A	p.Ala277Thr	missense	Exon 5 of 7	NP_056287.1	Q9GZV5
	WWTR1	NM_001168278.3		c.829G>A	p.Ala277Thr	missense	Exon 6 of 8	NP_001161750.1	Q9GZV5
	WWTR1	NM_001168280.3		c.829G>A	p.Ala277Thr	missense	Exon 5 of 7	NP_001161752.1	Q9GZV5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWTR1	ENST00000360632.8	TSL:1 MANE Select	c.829G>A	p.Ala277Thr	missense	Exon 5 of 7	ENSP00000353847.3	Q9GZV5
	WWTR1	ENST00000465804.5	TSL:2	c.829G>A	p.Ala277Thr	missense	Exon 6 of 8	ENSP00000419465.1	Q9GZV5
	WWTR1	ENST00000467467.5	TSL:5	c.829G>A	p.Ala277Thr	missense	Exon 5 of 7	ENSP00000419234.1	Q9GZV5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.60	N
PhyloP100		1.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.093
Sift	Benign	0.74	T
Sift4G	Benign	0.58	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.13		Gain of glycosylation at A277 (P = 0.0318)
MVP		0.068
MPC		0.46
ClinPred		0.15	T
GERP RS		3.8
Varity_R		0.042
gMVP		0.19
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs149464192; hg19: chr3-149245699;