3-149657083-C-A

Variant names:

• chr3-149657083-C-A
• rs1713282358
• NM_015472.6:c.224G>T

Variant summary

Our verdict is Likely benign. The variant received -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. 15/22 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: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.398
• 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]

WWTR1-AS1 (HGNC:41035): (WWTR1 antisense RNA 1)

ENSG00000301802 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1970979).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

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.224G>T	p.Gly75Val	missense	Exon 2 of 7	NP_056287.1	Q9GZV5
	WWTR1	NM_001168278.3		c.224G>T	p.Gly75Val	missense	Exon 3 of 8	NP_001161750.1	Q9GZV5
	WWTR1	NM_001168280.3		c.224G>T	p.Gly75Val	missense	Exon 2 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.224G>T	p.Gly75Val	missense	Exon 2 of 7	ENSP00000353847.3	Q9GZV5
	WWTR1-AS1	ENST00000495094.1	TSL:1	n.64C>A		non_coding_transcript_exon	Exon 1 of 2
	WWTR1	ENST00000465804.5	TSL:2	c.224G>T	p.Gly75Val	missense	Exon 3 of 8	ENSP00000419465.1	Q9GZV5

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

African (AFR) AF: 0.00 AC: 0 AN: 32928

American (AMR) AF: 0.00 AC: 0 AN: 38524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25398

East Asian (EAS) AF: 0.00 AC: 0 AN: 38046

South Asian (SAS) AF: 0.00 AC: 0 AN: 82314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42242

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5722

European-Non Finnish (NFE) AF: 0.0000156 AC: 17 AN: 1093124

Other (OTH) AF: 0.0000170 AC: 1 AN: 58968

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.13
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.40
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.098
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.032	D
Polyphen		0.91	P
Vest4		0.29
MutPred		0.26		Loss of catalytic residue at G75 (P = 0.0171)
MVP		0.11
MPC		1.5
ClinPred		0.73	D
GERP RS		3.7
PromoterAI		-0.045	Neutral
Varity_R		0.17
gMVP		0.36
Mutation Taster		=77/23	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: rs1713282358; hg19: chr3-149374870;