3-13818996-T-C

Variant names:

• chr3-13818996-T-C
• NM_004625.4:c.998A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_004625.4(WNT7A):​c.998A>G​(p.Tyr333Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,898 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: WNT7A NM_004625.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11
• Publications: 0 publications found

Genes affected

WNT7A (HGNC:12786): (Wnt family member 7A) This gene is a member of the WNT gene family, which consists of structurally related genes that 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 involved in the development of the anterior-posterior axis in the female reproductive tract, and also plays a critical role in uterine smooth muscle pattering and maintenance of adult uterine function. Mutations in this gene are associated with Fuhrmann and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndromes. [provided by RefSeq, Jul 2008]

WNT7A Gene-Disease associations (from GenCC):

• Fuhrmann syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• phocomelia, Schinzel type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.3439 (below the threshold of 3.09). Trascript score misZ: 1.655 (below the threshold of 3.09). GenCC associations: The gene is linked to Fuhrmann syndrome, phocomelia, Schinzel type.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT7A	NM_004625.4	c.998A>G	p.Tyr333Cys	missense_variant	Exon 4 of 4	ENST00000285018.5	NP_004616.2
WNT7A	XM_011534091.3	c.797A>G	p.Tyr266Cys	missense_variant	Exon 5 of 5		XP_011532393.1
WNT7A	XM_047448863.1	c.797A>G	p.Tyr266Cys	missense_variant	Exon 4 of 4		XP_047304819.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT7A	ENST00000285018.5	c.998A>G	p.Tyr333Cys	missense_variant	Exon 4 of 4	1	NM_004625.4	ENSP00000285018.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456898 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723730

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.0000448 AC: 2 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108198

Other (OTH) AF: 0.00 AC: 0 AN: 60154

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 333 of the WNT7A protein (p.Tyr333Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with WNT7A-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt WNT7A protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		2.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.63
Sift	Benign	0.13	T
Sift4G	Benign	0.069	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.69		Gain of sheet (P = 0.0827);
MVP		0.73
MPC		1.7
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.75
gMVP		0.65
Mutation Taster		=64/36	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

hg19: chr3-13860493;