1-63415881-C-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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013339.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG6	NM_013339.4	MANE Select	c.911C>T	p.Ser304Phe	missense	Exon 11 of 15	NP_037471.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG6	ENST00000263440.6	TSL:5 MANE Select	c.911C>T	p.Ser304Phe	missense	Exon 11 of 15	ENSP00000263440.5
	ALG6	ENST00000948329.1		c.911C>T	p.Ser304Phe	missense	Exon 11 of 15	ENSP00000618388.1
	ALG6	ENST00000920026.1		c.896C>T	p.Ser299Phe	missense	Exon 11 of 15	ENSP00000590085.1

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	ALG6-congenital disorder of glycosylation 1C (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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;