7-121338929-G-A

Variant names:

• chr7-121338929-G-A
• rs183788812
• NM_057168.2:c.682G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_057168.2(WNT16):​c.682G>A​(p.Gly228Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,614,036 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: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: WNT16 NM_057168.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

WNT16 (HGNC:16267): (Wnt family member 16) The WNT gene family consists of structurally related genes which 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 a member of the WNT gene family. It contains two transcript variants diverging at the 5' termini. These two variants are proposed to be the products of separate promoters and not to be splice variants from a single promoter. They are differentially expressed in normal tissues, one of which (variant 2) is expressed at significant levels only in the pancreas, whereas another one (variant 1) is expressed more ubiquitously with highest levels in adult kidney, placenta, brain, heart, and spleen. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT16	NM_057168.2	c.682G>A	p.Gly228Ser	missense_variant	Exon 4 of 4	ENST00000222462.3	NP_476509.1
WNT16	NM_016087.2	c.652G>A	p.Gly218Ser	missense_variant	Exon 4 of 4		NP_057171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT16	ENST00000222462.3	c.682G>A	p.Gly228Ser	missense_variant	Exon 4 of 4	1	NM_057168.2	ENSP00000222462.2
WNT16	ENST00000361301.6	c.652G>A	p.Gly218Ser	missense_variant	Exon 4 of 4	1		ENSP00000355065.2

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 250798 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135604

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000406

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000297 AC: 434 AN: 1461730 Hom.: 0 Cov.: 30 AF XY: 0.000292 AC XY: 212 AN XY: 727174

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000370

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74474

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000265 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.682G>A (p.G228S) alteration is located in exon 4 (coding exon 4) of the WNT16 gene. This alteration results from a G to A substitution at nucleotide position 682, causing the glycine (G) at amino acid position 228 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	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.5	.;H
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.050	T;T
Polyphen		1.0	D;D
Vest4		0.82
MVP		0.98
MPC		0.65
ClinPred		0.72	D
GERP RS		5.5
Varity_R		0.82
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs183788812; hg19: chr7-120978983;