11-111786460-G-C

Variant names:

• chr11-111786460-G-C
• rs77191760
• NM_024740.2:c.1794C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The ENST00000616540.5(ALG9):​c.1794C>G​(p.Tyr598*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y598Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALG9 ENST00000616540.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.466
• Publications: 0 publications found

Genes affected

ALG9 (HGNC:15672): (ALG9 alpha-1,2-mannosyltransferase) This gene encodes an alpha-1,2-mannosyltransferase enzyme that functions in lipid-linked oligosaccharide assembly. Mutations in this gene result in congenital disorder of glycosylation type Il. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ALG9 Gene-Disease associations (from GenCC):

• ALG9-associated autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• ALG9-congenital disorder of glycosylation

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet
• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Gillessen-Kaesbach-Nishimura syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ENSG00000258529 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0339 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000616540.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG9	NM_024740.2	MANE Select	c.1794C>G	p.Tyr598*	stop_gained	Exon 15 of 15	NP_079016.2
	ALG9	NM_001441203.1		c.1794C>G	p.Tyr598*	stop_gained	Exon 15 of 16	NP_001428132.1
	ALG9	NM_001352417.1		c.1773C>G	p.Tyr591*	stop_gained	Exon 15 of 16	NP_001339346.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG9	ENST00000616540.5	TSL:1 MANE Select	c.1794C>G	p.Tyr598*	stop_gained	Exon 15 of 15	ENSP00000482437.1
	ENSG00000258529	ENST00000622211.4	TSL:2	c.2472C>G	p.Tyr824*	stop_gained	Exon 19 of 19	ENSP00000482396.1
	ALG9	ENST00000614444.4	TSL:1	c.1773C>G	p.Tyr591*	stop_gained	Exon 15 of 15	ENSP00000484200.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Benign	0.15
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.64	D
PhyloP100		0.47
Vest4		0.47
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=29/171	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: rs77191760; hg19: chr11-111657184;