3-149526063-A-T

Position:

• chr3-149526063-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015472.6(WWTR1):​c.968T>A​(p.Val323Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,322 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • 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: 8.94

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WWTR1	NM_015472.6	c.968T>A	p.Val323Asp	missense_variant	6/7	ENST00000360632.8	NP_056287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WWTR1	ENST00000360632.8	c.968T>A	p.Val323Asp	missense_variant	6/7	1	NM_015472.6	ENSP00000353847.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458322 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725482

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2024

The c.968T>A (p.V323D) alteration is located in exon 6 (coding exon 5) of the WWTR1 gene. This alteration results from a T to A substitution at nucleotide position 968, causing the valine (V) at amino acid position 323 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	D;D;D;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;.;D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L;L;L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		0.84	P;P;P;.
Vest4		0.85
MutPred		0.30		Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);Gain of disorder (P = 0.0252);.;
MVP		0.39
MPC		1.0
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-149243850;