chr1-68145934-G-A

Variant names:

• chr1-68145934-G-A
• rs772685057
• NM_024911.7:c.1213C>T

Variant summary

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

The NM_024911.7(WLS):​c.1213C>T​(p.Arg405Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R405Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: WLS NM_024911.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38
• Publications: 0 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: 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 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.

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.1213C>T	p.Arg405Trp	missense	Exon 9 of 12	NP_079187.3
	WLS	NM_001002292.4		c.1207C>T	p.Arg403Trp	missense	Exon 9 of 12	NP_001002292.3	Q5T9L3-2
	WLS	NM_001193334.1		c.940C>T	p.Arg314Trp	missense	Exon 8 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.1213C>T	p.Arg405Trp	missense	Exon 9 of 12	ENSP00000262348.4	Q5T9L3-1
	WLS	ENST00000354777.6	TSL:1	c.1207C>T	p.Arg403Trp	missense	Exon 9 of 12	ENSP00000346829.2	Q5T9L3-2
	WLS	ENST00000370976.7	TSL:1	c.940C>T	p.Arg314Trp	missense	Exon 8 of 11	ENSP00000360015.3	Q5T9L3-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251132 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000340 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

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	0.28
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.26
Sift	Benign	0.12	T
Sift4G	Benign	0.15	T
Polyphen		0.95	P
Vest4		0.85
MVP		0.60
MPC		0.21
ClinPred		0.95	D
GERP RS		3.3
Varity_R		0.23
gMVP		0.89
Mutation Taster		=42/58	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: rs772685057; hg19: chr1-68611617;