Variant rs762811727 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024079.5(ALG8):c.535C>T(p.Arg179Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,606,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

ALG8
NM_024079.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.13

Variant links:

Genes affected

ALG8 (HGNC:23161): (ALG8 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the second glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation of proteins. Mutations in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ih). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ALG8 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-78119193-G-A is Pathogenic according to our data. Variant chr11-78119193-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 492977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG8	NM_024079.5 linkuse as main transcript	c.535C>T	p.Arg179Ter	stop_gained	5/13	ENST00000299626.10	NP_076984.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG8	ENST00000299626.10 linkuse as main transcript	c.535C>T	p.Arg179Ter	stop_gained	5/13	1	NM_024079.5	ENSP00000299626	P3	Q9BVK2-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250972

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000357

AC:

AN:

1454734

Hom.:

Cov.:

AF XY:

0.0000345

AC XY:

AN XY:

724102

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000425

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151966

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic liver disease 3 with or without kidney cysts

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 21, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained p.R179* in ALG8 (NM_024079.5) has been previously reported in heterozygous state in patients with polycystic liver disease (Besse W et al,2017). It has been submitted to ClinVar as Pathogenic based on the same. The p.R179* variant is observed in 1/16,224 (0.0062%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. -

ALG8-related disorder

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 22, 2023	The ALG8 c.535C>T variant is predicted to result in premature protein termination (p.Arg179*). This variant was firstly reported in the heterozygous state in a polycystic liver disease (PLD) patient who also has kidney cysts (Besse et al. 2017. PubMed ID: 28375157). In a later study of assessing the relationship between truncating ALG8 variants and polycystic kidney disease (PKD), individuals who are heterozygous for ALG8 pathogenic or likely pathogenic variants, including this variant, were shown to have increased risk of a mild (atypical) cystic kidney disease phenotype on imaging (Apple et al. 2023. PubMed ID: 36574950). Of note, the majority of loss-of-function variants in ALG8 have been reported in association with autosomal recessive congenital disorder of glycosylation (Human Gene Mutation Database). This variant is reported in 7 of 282,326 alleles in the gnomAD database. Nonsense variants in ALG8 are expected to be pathogenic. This variant is interpreted as likely pathogenic for autosomal recessive ALG8-related disorders. For autosomal dominant polycystic kidney-spectrum phenotype, however, it is currently uncertain since there is limited evidence to support the gene-disease relationship (ALG8 at https://www.clinicalgenome.org/). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 22, 2023	PVS1, PS3_Moderate -

ALG8 congenital disorder of glycosylation;C4693472:Polycystic liver disease 3 with or without kidney cysts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 20, 2022

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 18, 2023

PP2, PVS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.92

MutationTaster

Benign

1.0

A;A

Vest4

0.94

GERP RS

4.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over