rs983034

Variant names:

• chr1-68137903-C-T
• rs983034
• NM_024911.7:c.1393G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 35 publications found

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

Our verdict: Benign. The variant received -11 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.6033 (below the threshold of 3.09). Trascript score misZ: 1.7209 (below the threshold of 3.09). GenCC associations: The gene is linked to Zaki syndrome.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024911.7. 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
	WLS	NM_024911.7	MANE Select	c.1393G>A	p.Val465Ile	missense	Exon 11 of 12	NP_079187.3
	WLS	NM_001002292.4		c.1387G>A	p.Val463Ile	missense	Exon 11 of 12	NP_001002292.3	Q5T9L3-2
	WLS	NM_001193334.1		c.1120G>A	p.Val374Ile	missense	Exon 10 of 11	NP_001180263.1	Q5T9L3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WLS	ENST00000262348.9	TSL:1 MANE Select	c.1393G>A	p.Val465Ile	missense	Exon 11 of 12	ENSP00000262348.4	Q5T9L3-1
	WLS	ENST00000354777.6	TSL:1	c.1387G>A	p.Val463Ile	missense	Exon 11 of 12	ENSP00000346829.2	Q5T9L3-2
	WLS	ENST00000370976.7	TSL:1	c.1120G>A	p.Val374Ile	missense	Exon 10 of 11	ENSP00000360015.3	Q5T9L3-3

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

GnomAD2 exomes AF: 0.349 AC: 87538 AN: 251104 AF XY: 0.354

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 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

African (AFR) AF: 0.133 AC: 4438 AN: 33458

American (AMR) AF: 0.399 AC: 17851 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 10412 AN: 26118

East Asian (EAS) AF: 0.142 AC: 5649 AN: 39694

South Asian (SAS) AF: 0.364 AC: 31401 AN: 86240

European-Finnish (FIN) AF: 0.327 AC: 17486 AN: 53402

Middle Eastern (MID) AF: 0.346 AC: 1994 AN: 5766

European-Non Finnish (NFE) AF: 0.394 AC: 437590 AN: 1111718

Other (OTH) AF: 0.351 AC: 21204 AN: 60376

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

African (AFR) AF: 0.145 AC: 6032 AN: 41504

American (AMR) AF: 0.361 AC: 5507 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1383 AN: 3470

East Asian (EAS) AF: 0.146 AC: 755 AN: 5170

South Asian (SAS) AF: 0.337 AC: 1618 AN: 4806

European-Finnish (FIN) AF: 0.324 AC: 3412 AN: 10546

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26771 AN: 67940

Other (OTH) AF: 0.346 AC: 728 AN: 2106

Alfa AF: 0.367 Hom.: 48613

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 v4.9

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
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.86
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.057
Sift	Benign	0.66	T
Sift4G	Benign	0.52	T
Polyphen		0.0010	B
Vest4		0.016
MPC		0.15
ClinPred		0.0098	T
GERP RS		4.5
Varity_R		0.024
gMVP		0.24
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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