rs121908653

Variant names:

• chr1-22142888-A-G
• rs121908653
• NM_030761.5:c.35T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_030761.5(WNT4):​c.35T>C​(p.Leu12Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000094 in 1,063,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.4e-7 (0 hom.)
• Consequence: WNT4 NM_030761.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.210
• Publications: 10 publications found

Genes affected

WNT4 (HGNC:12783): (Wnt family member 4) The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family, and is the first signaling molecule shown to influence the sex-determination cascade. It encodes a protein which shows 98% amino acid identity to the Wnt4 protein of mouse and rat. This gene and a nuclear receptor known to antagonize the testis-determining factor play a concerted role in both the control of female development and the prevention of testes formation. This gene and another two family members, WNT2 and WNT7B, may be associated with abnormal proliferation in breast tissue. Mutations in this gene can result in Rokitansky-Kuster-Hauser syndrome and in SERKAL syndrome. [provided by RefSeq, Jul 2008]

WNT4 Gene-Disease associations (from GenCC):

• mullerian aplasia and hyperandrogenism

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• SERKAL syndrome

  Inheritance: AR, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000285873 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant 1-22142888-A-G is Pathogenic according to our data. Variant chr1-22142888-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6311.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT4	NM_030761.5	c.35T>C	p.Leu12Pro	missense_variant	Exon 1 of 5	ENST00000290167.11	NP_110388.2
LOC105376845	XR_947051.3	n.39A>G		non_coding_transcript_exon_variant	Exon 1 of 5
LOC105376845	XR_947056.2	n.39A>G		non_coding_transcript_exon_variant	Exon 1 of 5
LOC105376845	XR_947050.1	n.53+1883A>G		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT4	ENST00000290167.11	c.35T>C	p.Leu12Pro	missense_variant	Exon 1 of 5	1	NM_030761.5	ENSP00000290167.5
ENSG00000285873	ENST00000648968.1	n.39A>G		non_coding_transcript_exon_variant	Exon 1 of 5
ENSG00000285873	ENST00000808862.1	n.20A>G		non_coding_transcript_exon_variant	Exon 1 of 5
WNT4	ENST00000441048.1	c.-89+844T>C		intron_variant	Intron 1 of 2	5		ENSP00000388925.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.40e-7 AC: 1 AN: 1063424 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 521314

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20030

American (AMR) AF: 0.00 AC: 0 AN: 21266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13922

East Asian (EAS) AF: 0.00 AC: 0 AN: 6254

South Asian (SAS) AF: 0.00 AC: 0 AN: 68130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2492

European-Non Finnish (NFE) AF: 0.00000114 AC: 1 AN: 879524

Other (OTH) AF: 0.00 AC: 0 AN: 37248

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mullerian aplasia and hyperandrogenism Pathogenic:1

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.21
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.012	D
Polyphen		0.21	B
Vest4		0.45
MutPred		0.89		Loss of stability (P = 0.0062);
MVP		0.92
MPC		1.3
ClinPred		0.30	T
GERP RS		2.2
PromoterAI		-0.063	Neutral
Varity_R		0.72
gMVP		0.71
Mutation Taster		=23/77	disease causing (ClinVar)

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: rs121908653; hg19: chr1-22469381;