NM_013339.4:c.911C>T

Variant names:

• chr1-63415881-C-T
• rs4630153
• NM_013339.4:c.911C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_013339.4(ALG6):​c.911C>T​(p.Ser304Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 1,601,814 control chromosomes in the GnomAD database, including 416,603 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44209 hom., cov: 33)
  • Exomes 𝑓: 0.71 (372394 hom.)
• Consequence: ALG6 NM_013339.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.653
• Publications: 55 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-63415881-C-T is Benign according to our data. Variant chr1-63415881-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG6	NM_013339.4	c.911C>T	p.Ser304Phe	missense_variant	Exon 11 of 15	ENST00000263440.6	NP_037471.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG6	ENST00000263440.6	c.911C>T	p.Ser304Phe	missense_variant	Exon 11 of 15	5	NM_013339.4	ENSP00000263440.5

Frequencies

GnomAD3 genomes AF: 0.757 AC: 115079 AN: 151958 Hom.: 44156 Cov.: 33

Gnomad AFR AF: 0.866

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.765

Gnomad ASJ AF: 0.778

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.864

Gnomad FIN AF: 0.682

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.767

GnomAD2 exomes AF: 0.754 AC: 187926 AN: 249388 AF XY: 0.752

Gnomad AFR exome AF: 0.870

Gnomad AMR exome AF: 0.823

Gnomad ASJ exome AF: 0.777

Gnomad EAS exome AF: 0.861

Gnomad FIN exome AF: 0.675

Gnomad NFE exome AF: 0.684

Gnomad OTH exome AF: 0.750

GnomAD4 exome AF: 0.714 AC: 1034456 AN: 1449738 Hom.: 372394 Cov.: 31 AF XY: 0.718 AC XY: 518209 AN XY: 721786

African (AFR) AF: 0.871 AC: 28919 AN: 33196

American (AMR) AF: 0.816 AC: 36434 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 20322 AN: 26028

East Asian (EAS) AF: 0.836 AC: 32983 AN: 39474

South Asian (SAS) AF: 0.858 AC: 73647 AN: 85792

European-Finnish (FIN) AF: 0.676 AC: 36041 AN: 53314

Middle Eastern (MID) AF: 0.825 AC: 4738 AN: 5746

European-Non Finnish (NFE) AF: 0.687 AC: 756987 AN: 1101632

Other (OTH) AF: 0.741 AC: 44385 AN: 59930

GnomAD4 genome AF: 0.757 AC: 115188 AN: 152076 Hom.: 44209 Cov.: 33 AF XY: 0.759 AC XY: 56404 AN XY: 74340

African (AFR) AF: 0.867 AC: 35986 AN: 41524

American (AMR) AF: 0.765 AC: 11704 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.778 AC: 2699 AN: 3468

East Asian (EAS) AF: 0.859 AC: 4444 AN: 5174

South Asian (SAS) AF: 0.864 AC: 4168 AN: 4826

European-Finnish (FIN) AF: 0.682 AC: 7190 AN: 10538

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46498 AN: 67940

Other (OTH) AF: 0.768 AC: 1621 AN: 2110

Alfa AF: 0.712 Hom.: 131152

Bravo AF: 0.769

TwinsUK AF: 0.684 AC: 2537

ALSPAC AF: 0.693 AC: 2672

ESP6500AA AF: 0.856 AC: 3769

ESP6500EA AF: 0.676 AC: 5809

ExAC AF: 0.750 AC: 91011

Asia WGS AF: 0.850 AC: 2947 AN: 3468

EpiCase AF: 0.703

EpiControl AF: 0.704

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 05, 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. -

Oct 04, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

ALG6-congenital disorder of glycosylation 1C Benign:4

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.39
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.16	.;T
MetaRNN	Benign	0.0000017	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		0.65
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.19
Sift	Benign	0.21	T;.
Sift4G	Benign	0.58	T;.
Vest4		0.061
MPC		0.32
ClinPred		0.0026	T
GERP RS		3.9
Varity_R		0.062
gMVP		0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: -8

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

Other links and lift over

dbSNP: rs4630153; hg19: chr1-63881552; COSMIC: COSV54765155; COSMIC: COSV54765155;