rs983034

Positions:

• chr1-68137903-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024911.7(WLS):​c.1393G>A​(p.Val465Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,613,486 control chromosomes in the GnomAD database, including 114,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.31 (8137 hom., cov: 32)
  • Exomes 𝑓: 0.37 (105967 hom.)
• Consequence: WLS NM_024911.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.861

Genes affected

WLS (HGNC:30238): (Wnt ligand secretion mediator) Enables Wnt-protein binding activity and identical protein binding activity. Involved in positive regulation of cell communication and protein transport. Located in several cellular components, including Golgi apparatus; early endosome; and endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

GNG12-AS1 (HGNC:43938): (GNG12, DIRAS3 and WLS antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034739375).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WLS	NM_024911.7	c.1393G>A	p.Val465Ile	missense_variant	11/12	ENST00000262348.9
GNG12-AS1	NR_040077.1	n.1075-394C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WLS	ENST00000262348.9	c.1393G>A	p.Val465Ile	missense_variant	11/12	1	NM_024911.7	P1
GNG12-AS1	ENST00000420587.5	n.1060-394C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46628 AN: 151894 Hom.: 8130 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.342

GnomAD3 exomes AF: 0.349 AC: 87538 AN: 251104 Hom.: 16384 AF XY: 0.354 AC XY: 48003 AN XY: 135702

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.405

Gnomad EAS exome AF: 0.144

Gnomad SAS exome AF: 0.360

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.375 AC: 548025 AN: 1461474 Hom.: 105967 Cov.: 46 AF XY: 0.376 AC XY: 273379 AN XY: 727068

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.399

Gnomad4 ASJ exome AF: 0.399

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.364

Gnomad4 FIN exome AF: 0.327

Gnomad4 NFE exome AF: 0.394

Gnomad4 OTH exome AF: 0.351

GnomAD4 genome AF: 0.307 AC: 46653 AN: 152012 Hom.: 8137 Cov.: 32 AF XY: 0.305 AC XY: 22648 AN XY: 74294

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.399

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.337

Gnomad4 FIN AF: 0.324

Gnomad4 NFE AF: 0.394

Gnomad4 OTH AF: 0.346

Alfa AF: 0.375 Hom.: 27911

Bravo AF: 0.303

TwinsUK AF: 0.388 AC: 1440

ALSPAC AF: 0.407 AC: 1568

ESP6500AA AF: 0.149 AC: 658

ESP6500EA AF: 0.396 AC: 3402

ExAC AF: 0.345 AC: 41865

Asia WGS AF: 0.231 AC: 802 AN: 3478

EpiCase AF: 0.391

EpiControl AF: 0.394

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	19
DANN	Benign	0.88
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.75	T;T;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.78	P;P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.21	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.66	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.016
MPC		0.15
ClinPred		0.0098	T
GERP RS		4.5
Varity_R		0.024
gMVP		0.24

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: rs983034; hg19: chr1-68603586; COSMIC: COSV52037496; COSMIC: COSV52037496;