3-13819110-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_004625.4(WNT7A):c.884A>G(p.Asn295Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,818 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: 0.0000062 (0 hom.)
• Consequence: WNT7A NM_004625.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity WNT7A_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNT7A	NM_004625.4	c.884A>G	p.Asn295Ser	missense_variant	4/4	ENST00000285018.5
WNT7A	XM_011534091.3	c.683A>G	p.Asn228Ser	missense_variant	5/5
WNT7A	XM_047448863.1	c.683A>G	p.Asn228Ser	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT7A	ENST00000285018.5	c.884A>G	p.Asn295Ser	missense_variant	4/4	1	NM_004625.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251352 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000616 AC: 9 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.884A>G (p.N295S) alteration is located in exon 4 (coding exon 4) of the WNT7A gene. This alteration results from a A to G substitution at nucleotide position 884, causing the asparagine (N) at amino acid position 295 to be replaced by a serine (S). 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	Benign	0.093
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.69
Sift	Benign	0.091	T
Sift4G	Uncertain	0.053	T
Polyphen		0.93	P
Vest4		0.71
MVP		0.96
MPC		1.5
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.65
gMVP		0.74

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

LitVar

Other links and lift over

dbSNP: rs957235068; hg19: chr3-13860607;