22-45931130-T-G

Position:

• chr22-45931130-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_058238.3(WNT7B):​c.538A>C​(p.Met180Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: WNT7B NM_058238.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.72

Genes affected

WNT7B (HGNC:12787): (Wnt family member 7B) 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. Among members of the human WNT family, this gene product is most similar to WNT7A protein. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNT7B	NM_058238.3	c.538A>C	p.Met180Leu	missense_variant	3/4	ENST00000339464.9	NP_478679.1
WNT7B	NM_001410806.1	c.550A>C	p.Met184Leu	missense_variant	3/4		NP_001397735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNT7B	ENST00000339464.9	c.538A>C	p.Met180Leu	missense_variant	3/4	1	NM_058238.3	ENSP00000341032.4
WNT7B	ENST00000409496.7	c.550A>C	p.Met184Leu	missense_variant	3/4	2		ENSP00000386546.3
WNT7B	ENST00000410089.5	c.490A>C	p.Met164Leu	missense_variant	3/4	5		ENSP00000386781.1
WNT7B	ENST00000410058.1	c.538A>C	p.Met180Leu	missense_variant	3/4	3		ENSP00000387217.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Mar 07, 2024

The c.538A>C (p.M180L) alteration is located in exon 3 (coding exon 3) of the WNT7B gene. This alteration results from a A to C substitution at nucleotide position 538, causing the methionine (M) at amino acid position 180 to be replaced by a leucine (L). 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	0.86
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D;.;D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.7	M;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.84	P;P;.;.
Vest4		0.78
MutPred		0.82		.;Loss of catalytic residue at M184 (P = 0.028);.;.;
MVP		0.77
MPC		1.4
ClinPred		0.96	D
GERP RS		3.2
Varity_R		0.70
gMVP		0.83

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: chr22-46327010;