22-45923047-C-T

Variant names:

• chr22-45923047-C-T
• rs780469731
• NM_058238.3:c.859G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_058238.3(WNT7B):​c.859G>A​(p.Val287Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,460,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: WNT7B NM_058238.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58
• 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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3343794).

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.859G>A	p.Val287Met	missense	Exon 4 of 4	NP_478679.1	P56706
	WNT7B	NM_001410806.1		c.871G>A	p.Val291Met	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.859G>A	p.Val287Met	missense	Exon 4 of 4	ENSP00000341032.4	P56706
	WNT7B	ENST00000409496.7	TSL:2	c.871G>A	p.Val291Met	missense	Exon 4 of 4	ENSP00000386546.3	A8K0G1
	WNT7B	ENST00000410089.5	TSL:5	c.811G>A	p.Val271Met	missense	Exon 4 of 4	ENSP00000386781.1	B8A595

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 250240 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1460412 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 726436

African (AFR) AF: 0.0000896 AC: 3 AN: 33468

American (AMR) AF: 0.0000448 AC: 2 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111444

Other (OTH) AF: 0.0000331 AC: 2 AN: 60346

GnomAD4 genome Cov.: 34

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Benign	0.087
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.14	N
PhyloP100		2.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.18
Sift	Benign	0.090	T
Sift4G	Benign	0.082	T
Polyphen		0.25	B
Vest4		0.15
MutPred		0.52		Gain of disorder (P = 0.0481)
MVP		0.73
MPC		0.80
ClinPred		0.13	T
GERP RS		3.9
Varity_R		0.15
gMVP		0.25
Mutation Taster		=85/15	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

dbSNP: rs780469731; hg19: chr22-46318927;