rs35383149

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

32 publications found

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:

ITGB3BP (HGNC:6157): (integrin subunit beta 3 binding protein) This gene encodes a transcriptional coregulator that binds to and enhances the activity of members of the nuclear receptor families, thyroid hormone receptors and retinoid X receptors. This protein also acts as a corepressor of NF-kappaB-dependent signaling. This protein induces apoptosis in breast cancer cells through a caspase 2-mediated signaling pathway. This protein is also a component of the centromere-specific histone H3 variant nucleosome associated complex (CENP-NAC) and may be involved in mitotic progression by recruiting the histone H3 variant CENP-A to the centromere. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ITGB3BP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 30422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 90 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG6	NM_013339.4 link	c.391T>C	p.Tyr131His	missense_variant	Exon 6 of 15	ENST00000263440.6	NP_037471.2	Q9Y672

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG6	ENST00000263440.6 link	c.391T>C	p.Tyr131His	missense_variant	Exon 6 of 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

GnomAD2 exomes

AF:

0.0302

AC:

7589

AN:

251226

AF XY:

0.0304

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 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

African (AFR)

AF:

0.00628

AC:

210

AN:

33448

American (AMR)

AF:

0.0214

AC:

959

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0770

AC:

2010

AN:

26114

East Asian (EAS)

AF:

0.000101

AC:

AN:

39628

South Asian (SAS)

AF:

0.0137

AC:

1185

AN:

86236

European-Finnish (FIN)

AF:

0.0441

AC:

2355

AN:

53342

Middle Eastern (MID)

AF:

0.0245

AC:

140

AN:

5706

European-Non Finnish (NFE)

AF:

0.0381

AC:

42384

AN:

1111466

Other (OTH)

AF:

0.0352

AC:

2124

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2514

5028

7541

10055

12569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1552

3104

4656

6208

7760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0291

AC:

4424

AN:

152202

Hom.:

Cov.:

AF XY:

0.0296

AC XY:

2202

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00705

AC:

293

AN:

41568

American (AMR)

AF:

0.0388

AC:

592

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0765

AC:

265

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.0143

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0420

AC:

446

AN:

10626

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0388

AC:

2634

AN:

67936

Other (OTH)

AF:

0.0360

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

221

443

664

886

1107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0371

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 08, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 13, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2011

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:5

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 26, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Sep 03, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

ALG6-related disorder

Benign:1

Mar 15, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

4.0

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over