NM_024911.7:c.1175A>G

Variant names:

• chr1-68145972-T-C
• rs2100452147
• NM_024911.7:c.1175A>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_024911.7(WLS):​c.1175A>G​(p.Tyr392Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WLS NM_024911.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.67
• Publications: 2 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: Pathogenic. The variant received 13 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869
• PP5: Variant 1-68145972-T-C is Pathogenic according to our data. Variant chr1-68145972-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1098567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1175A>G	p.Tyr392Cys	missense	Exon 9 of 12	NP_079187.3
	WLS	NM_001002292.4		c.1169A>G	p.Tyr390Cys	missense	Exon 9 of 12	NP_001002292.3	Q5T9L3-2
	WLS	NM_001193334.1		c.902A>G	p.Tyr301Cys	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.1175A>G	p.Tyr392Cys	missense	Exon 9 of 12	ENSP00000262348.4	Q5T9L3-1
	WLS	ENST00000354777.6	TSL:1	c.1169A>G	p.Tyr390Cys	missense	Exon 9 of 12	ENSP00000346829.2	Q5T9L3-2
	WLS	ENST00000370976.7	TSL:1	c.902A>G	p.Tyr301Cys	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: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Zaki syndrome (2)
1	-	-	WLS syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.44		Loss of stability (P = 0.2221)
MVP		0.90
MPC		0.83
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.98
Mutation Taster		=9/91	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: rs2100452147; hg19: chr1-68611655;