chr3-149520981-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015472.6(WWTR1):​c.1027G>A​(p.Ala343Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,592,278 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. A343S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015779763).
• BS2: High AC in GnomAdExome4 at 26 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.1027G>A	p.Ala343Thr	missense	Exon 7 of 7	NP_056287.1	Q9GZV5
	WWTR1	NM_001168278.3		c.1027G>A	p.Ala343Thr	missense	Exon 8 of 8	NP_001161750.1	Q9GZV5
	WWTR1	NM_001168280.3		c.1027G>A	p.Ala343Thr	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>A	p.Ala343Thr	missense	Exon 7 of 7	ENSP00000353847.3	Q9GZV5
	WWTR1	ENST00000465804.5	TSL:2	c.1027G>A	p.Ala343Thr	missense	Exon 8 of 8	ENSP00000419465.1	Q9GZV5
	WWTR1	ENST00000467467.5	TSL:5	c.1027G>A	p.Ala343Thr	missense	Exon 7 of 7	ENSP00000419234.1	Q9GZV5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000613 AC: 14 AN: 228260 AF XY: 0.0000486

Gnomad AFR exome AF: 0.0000642

Gnomad AMR exome AF: 0.000142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000653

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000181 AC: 26 AN: 1440008 Hom.: 0 Cov.: 30 AF XY: 0.0000223 AC XY: 16 AN XY: 715950

African (AFR) AF: 0.0000627 AC: 2 AN: 31896

American (AMR) AF: 0.000153 AC: 6 AN: 39092

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

East Asian (EAS) AF: 0.0000764 AC: 3 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: 0.0000118 AC: 13 AN: 1104898

Other (OTH) AF: 0.0000168 AC: 1 AN: 59412

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74454

African (AFR) AF: 0.0000241 AC: 1 AN: 41548

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000357 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

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	0.063
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.76
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.082
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.035
Sift	Benign	0.57	T
Sift4G	Benign	0.64	T
Polyphen		0.15	B
Vest4		0.020
MVP		0.12
MPC		0.46
ClinPred		0.0061	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.19
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV105257563; COSMIC: COSV105257563;