chr1-68145984-C-G

Variant names:

• chr1-68145984-C-G
• NM_024911.7:c.1163G>C

Variant summary

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

The NM_024911.7(WLS):​c.1163G>C​(p.Cys388Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WLS NM_024911.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• 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.1163G>C	p.Cys388Ser	missense	Exon 9 of 12	NP_079187.3
	WLS	NM_001002292.4		c.1157G>C	p.Cys386Ser	missense	Exon 9 of 12	NP_001002292.3	Q5T9L3-2
	WLS	NM_001193334.1		c.890G>C	p.Cys297Ser	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.1163G>C	p.Cys388Ser	missense	Exon 9 of 12	ENSP00000262348.4	Q5T9L3-1
	WLS	ENST00000354777.6	TSL:1	c.1157G>C	p.Cys386Ser	missense	Exon 9 of 12	ENSP00000346829.2	Q5T9L3-2
	WLS	ENST00000370976.7	TSL:1	c.890G>C	p.Cys297Ser	missense	Exon 8 of 11	ENSP00000360015.3	Q5T9L3-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	Uncertain	0.56
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.31	N
PhyloP100		7.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.27
Sift	Benign	0.60	T
Sift4G	Benign	0.80	T
Polyphen		0.67	P
Vest4		0.89
MutPred		0.42		Loss of helix (P = 0.079)
MVP		0.58
MPC		0.30
ClinPred		0.54	D
GERP RS		5.4
Varity_R		0.34
gMVP		0.89
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr1-68611667;