22-45922876-C-T

Variant names:

• chr22-45922876-C-T
• rs775439780
• NM_058238.3:c.1030G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_058238.3(WNT7B):​c.1030G>A​(p.Glu344Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,601,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: WNT7B NM_058238.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76
• 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: Uncertain_significance. The variant received 3 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 multiple congenital anomalies/dysmorphic syndrome, Tourette syndrome.

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.1030G>A	p.Glu344Lys	missense	Exon 4 of 4	NP_478679.1	P56706
	WNT7B	NM_001410806.1		c.1042G>A	p.Glu348Lys	missense	Exon 4 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.1030G>A	p.Glu344Lys	missense	Exon 4 of 4	ENSP00000341032.4	P56706
	WNT7B	ENST00000409496.7	TSL:2	c.1042G>A	p.Glu348Lys	missense	Exon 4 of 4	ENSP00000386546.3	A8K0G1
	WNT7B	ENST00000410089.5	TSL:5	c.982G>A	p.Glu328Lys	missense	Exon 4 of 4	ENSP00000386781.1	B8A595

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249000 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.0000138 AC: 20 AN: 1449746 Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 10 AN XY: 718722

African (AFR) AF: 0.0000301 AC: 1 AN: 33268

American (AMR) AF: 0.0000450 AC: 2 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39324

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.0000145 AC: 16 AN: 1103088

Other (OTH) AF: 0.00 AC: 0 AN: 59768

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.59
MVP		0.93
MPC		1.9
ClinPred		0.97	D
GERP RS		4.4
Varity_R		0.71
gMVP		0.58
Mutation Taster		=40/60	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: rs775439780; hg19: chr22-46318756;