1-63406361-T-C

Position:

chr1-63406361-T-C

Variant summary

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

The NM_013339.4(ALG6):c.391T>C(p.Tyr131His) variant causes a missense change. The variant allele was found at a frequency of 0.0346 in 1,613,214 control chromosomes in the GnomAD database, including 1,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 90 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1039 hom. )

Consequence

ALG6
NM_013339.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:14

Conservation

PhyloP100: 3.96

Variant links:

Genes affected

ALG6 (HGNC:23157): (ALG6 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the first glucose residue to the growing lipid-linked oligosaccharide precursor of N-linked glycosylation. Mutations in this gene are associated with congenital disorders of glycosylation type Ic. [provided by RefSeq, Jul 2008]

ALG6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009405732).

BP6

Variant 1-63406361-T-C is Benign according to our data. Variant chr1-63406361-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 30422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-63406361-T-C is described in Lovd as [Benign]. Variant chr1-63406361-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0291 (4424/152202) while in subpopulation NFE AF= 0.0388 (2634/67936). AF 95% confidence interval is 0.0375. There are 90 homozygotes in gnomad4. There are 2202 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 90 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG6	NM_013339.4 linkuse as main transcript	c.391T>C	p.Tyr131His	missense_variant	6/15	ENST00000263440.6	NP_037471.2	Q9Y672

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG6	ENST00000263440.6 linkuse as main transcript	c.391T>C	p.Tyr131His	missense_variant	6/15	5	NM_013339.4	ENSP00000263440.5		Q9Y672

Frequencies

GnomAD3 genomes

AF:

0.0291

AC:

4425

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00707

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0388

Gnomad ASJ

AF:

0.0765

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.0420

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0388

Gnomad OTH

AF:

0.0369

GnomAD3 exomes

AF:

0.0302

AC:

7589

AN:

251226

Hom.:

162

AF XY:

0.0304

AC XY:

4122

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.0210

Gnomad ASJ exome

AF:

0.0732

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0128

Gnomad FIN exome

AF:

0.0437

Gnomad NFE exome

AF:

0.0391

Gnomad OTH exome

AF:

0.0404

GnomAD4 exome

AF:

0.0352

AC:

51371

AN:

1461012

Hom.:

1039

Cov.:

AF XY:

0.0350

AC XY:

25409

AN XY:

726842

show subpopulations

Gnomad4 AFR exome

AF:

0.00628

Gnomad4 AMR exome

AF:

0.0214

Gnomad4 ASJ exome

AF:

0.0770

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0137

Gnomad4 FIN exome

AF:

0.0441

Gnomad4 NFE exome

AF:

0.0381

Gnomad4 OTH exome

AF:

0.0352

GnomAD4 genome

AF:

0.0291

AC:

4424

AN:

152202

Hom.:

Cov.:

AF XY:

0.0296

AC XY:

2202

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00705

Gnomad4 AMR

AF:

0.0388

Gnomad4 ASJ

AF:

0.0765

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0143

Gnomad4 FIN

AF:

0.0420

Gnomad4 NFE

AF:

0.0388

Gnomad4 OTH

AF:

0.0360

Alfa

AF:

0.0377

Hom.:

Bravo

AF:

0.0280

TwinsUK

AF:

0.0375

AC:

139

ALSPAC

AF:

0.0389

AC:

150

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0412

AC:

354

ExAC

AF:

0.0286

AC:

3478

Asia WGS

AF:

0.00636

AC:

AN:

3476

EpiCase

AF:

0.0410

EpiControl

AF:

0.0453

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ALG6-congenital disorder of glycosylation 1C

Uncertain:1Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 08, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 13, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	May 01, 2011	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

ALG6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

D;D

Eigen

Benign

-0.031

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.84

.;T

MetaRNN

Benign

0.0094

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Pathogenic

3.2

M;M

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.41

Sift

Benign

0.064

T;T

Sift4G

Benign

0.11

T;T

Vest4

0.21

MPC

0.38

ClinPred

0.072

GERP RS

4.8

Varity_R

0.75

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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