rs1459922346

Variant names:

• chr3-149657012-C-G
• rs1459922346
• NM_015472.6:c.295G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-149657012-C-G
• chr3-149657012-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015472.6(WWTR1):​c.295G>C​(p.Gly99Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. G99S) 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: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• 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]

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

ENSG00000301802 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13428938).

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.295G>C	p.Gly99Arg	missense	Exon 2 of 7	NP_056287.1	Q9GZV5
	WWTR1	NM_001168278.3		c.295G>C	p.Gly99Arg	missense	Exon 3 of 8	NP_001161750.1	Q9GZV5
	WWTR1	NM_001168280.3		c.295G>C	p.Gly99Arg	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.295G>C	p.Gly99Arg	missense	Exon 2 of 7	ENSP00000353847.3	Q9GZV5
	WWTR1	ENST00000465804.5	TSL:2	c.295G>C	p.Gly99Arg	missense	Exon 3 of 8	ENSP00000419465.1	Q9GZV5
	WWTR1	ENST00000467467.5	TSL:5	c.295G>C	p.Gly99Arg	missense	Exon 2 of 7	ENSP00000419234.1	Q9GZV5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000467 AC: 1 AN: 214264 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000308

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442972 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 717570

African (AFR) AF: 0.00 AC: 0 AN: 33236

American (AMR) AF: 0.0000230 AC: 1 AN: 43418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25724

East Asian (EAS) AF: 0.00 AC: 0 AN: 39410

South Asian (SAS) AF: 0.00 AC: 0 AN: 85314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107634

Other (OTH) AF: 0.00 AC: 0 AN: 59786

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.029
Sift	Uncertain	0.029	D
Sift4G	Benign	0.60	T
Polyphen		0.0060	B
Vest4		0.15
MutPred		0.31		Gain of MoRF binding (P = 0.0075)
MVP		0.093
MPC		1.0
ClinPred		0.65	D
GERP RS		4.2
PromoterAI		-0.035	Neutral
Varity_R		0.076
gMVP		0.43
Mutation Taster		=86/14	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: rs1459922346; hg19: chr3-149374799;