22-45931274-C-A

Variant names:

• chr22-45931274-C-A
• rs768926470
• NM_058238.3:c.394G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_058238.3(WNT7B):​c.394G>T​(p.Gly132Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G132S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WNT7B NM_058238.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.96
• Publications: 0 publications found

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]

WNT7B Gene-Disease associations (from GenCC):

• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.9927 (below the threshold of 3.09). Trascript score misZ: 1.4346 (below the threshold of 3.09). GenCC associations: The gene is linked to Tourette syndrome, multiple congenital anomalies/dysmorphic syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058238.3. 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
	WNT7B	NM_058238.3	MANE Select	c.394G>T	p.Gly132Cys	missense	Exon 3 of 4	NP_478679.1	P56706
	WNT7B	NM_001410806.1		c.406G>T	p.Gly136Cys	missense	Exon 3 of 4	NP_001397735.1	A8K0G1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT7B	ENST00000339464.9	TSL:1 MANE Select	c.394G>T	p.Gly132Cys	missense	Exon 3 of 4	ENSP00000341032.4	P56706
	WNT7B	ENST00000409496.7	TSL:2	c.406G>T	p.Gly136Cys	missense	Exon 3 of 4	ENSP00000386546.3	A8K0G1
	WNT7B	ENST00000410089.5	TSL:5	c.346G>T	p.Gly116Cys	missense	Exon 3 of 4	ENSP00000386781.1	B8A595

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238174 AF XY: 0.00

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.00

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: 6.91e-7 AC: 1 AN: 1446316 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719988

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111686

Other (OTH) AF: 0.00 AC: 0 AN: 60284

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.0
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.92		Loss of disorder (P = 0.0447)
MVP		0.97
MPC		1.8
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.83
gMVP		0.89
Mutation Taster		=19/81	disease causing

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: rs768926470; hg19: chr22-46327154;