chr11-78112652-A-G

Position:

chr11-78112652-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000299626.10(ALG8):c.896T>C(p.Ile299Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00113 in 1,613,828 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I299I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0058 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 9 hom. )

Consequence

ALG8
ENST00000299626.10 missense, splice_region

Scores

Splicing: ADA: 0.0002569

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.43

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0097923875).

BP6

Variant 11-78112652-A-G is Benign according to our data. Variant chr11-78112652-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 306218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00577 (879/152302) while in subpopulation AFR AF= 0.0201 (834/41564). AF 95% confidence interval is 0.0189. There are 8 homozygotes in gnomad4. There are 432 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG8	NM_024079.5 linkuse as main transcript	c.896T>C	p.Ile299Thr	missense_variant, splice_region_variant	8/13	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.896T>C	p.Ile299Thr	missense_variant, splice_region_variant	8/13	1	NM_024079.5	ENSP00000299626	P3	Q9BVK2-1

Frequencies

GnomAD3 genomes

AF:

0.00576

AC:

877

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0201

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00162

AC:

408

AN:

251420

Hom.:

AF XY:

0.00128

AC XY:

174

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.0218

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000647

AC:

946

AN:

1461526

Hom.:

Cov.:

AF XY:

0.000576

AC XY:

419

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.0216

Gnomad4 AMR exome

AF:

0.00143

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.00577

AC:

879

AN:

152302

Hom.:

Cov.:

AF XY:

0.00580

AC XY:

432

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0201

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00113

Hom.:

Bravo

AF:

0.00687

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00207

AC:

251

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ALG8 congenital disorder of glycosylation

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.50

D;.;.;D

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

T;.;T;T

MetaRNN

Benign

0.0098

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.8

D;D;.;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.022

D;D;.;D

Sift4G

Benign

0.16

T;T;T;.

Polyphen

0.0010

B;.;.;.

Vest4

0.29

MVP

0.97

MPC

0.19

ClinPred

0.039

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00026

dbscSNV1_RF

Benign

0.050

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

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