rs188215356

Variant names:

• chr3-149520981-C-A
• rs188215356
• NM_015472.6:c.1027G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-149520981-C-A
• chr3-149520981-C-T

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.1027G>T​(p.Ala343Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A343T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WWTR1 NM_015472.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0820
• 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=0.02140674).

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.1027G>T	p.Ala343Ser	missense	Exon 7 of 7	NP_056287.1	Q9GZV5
	WWTR1	NM_001168278.3		c.1027G>T	p.Ala343Ser	missense	Exon 8 of 8	NP_001161750.1	Q9GZV5
	WWTR1	NM_001168280.3		c.1027G>T	p.Ala343Ser	missense	Exon 7 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.1027G>T	p.Ala343Ser	missense	Exon 7 of 7	ENSP00000353847.3	Q9GZV5
	WWTR1	ENST00000465804.5	TSL:2	c.1027G>T	p.Ala343Ser	missense	Exon 8 of 8	ENSP00000419465.1	Q9GZV5
	WWTR1	ENST00000467467.5	TSL:5	c.1027G>T	p.Ala343Ser	missense	Exon 7 of 7	ENSP00000419234.1	Q9GZV5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440008 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 715950

African (AFR) AF: 0.00 AC: 0 AN: 31896

American (AMR) AF: 0.00 AC: 0 AN: 39092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39288

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104898

Other (OTH) AF: 0.00 AC: 0 AN: 59412

GnomAD4 genome Cov.: 33

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	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	15
DANN	Benign	0.74
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.082
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.016
Sift	Benign	0.74	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.040
MutPred		0.15		Loss of catalytic residue at A343 (P = 0.0077)
MVP		0.093
MPC		0.44
ClinPred		0.017	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.22
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs188215356; hg19: chr3-149238768;