rs61755863

Variant names:

• chr1-63411996-A-G
• rs61755863
• NM_013339.4:c.751A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013339.4(ALG6):​c.751A>G​(p.Thr251Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,070 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (11 hom.)
• Consequence: ALG6 NM_013339.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.03
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059894323).
• BP6: Variant 1-63411996-A-G is Benign according to our data. Variant chr1-63411996-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128354.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 = 0.00655 (997/152232) while in subpopulation AFR AF = 0.0225 (933/41530). AF 95% confidence interval is 0.0213. There are 8 homozygotes in GnomAd4. There are 465 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

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.751A>G	p.Thr251Ala	missense	Exon 9 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.751A>G	p.Thr251Ala	missense	Exon 9 of 15	ENSP00000263440.5	Q9Y672
	ALG6	ENST00000948329.1		c.751A>G	p.Thr251Ala	missense	Exon 9 of 15	ENSP00000618388.1
	ALG6	ENST00000920026.1		c.736A>G	p.Thr246Ala	missense	Exon 9 of 15	ENSP00000590085.1

Frequencies

GnomAD3 genomes AF: 0.00650 AC: 989 AN: 152114 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00159 AC: 400 AN: 251274 AF XY: 0.00110

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000692 AC: 1011 AN: 1461838 Hom.: 11 Cov.: 31 AF XY: 0.000613 AC XY: 446 AN XY: 727232

African (AFR) AF: 0.0228 AC: 764 AN: 33470

American (AMR) AF: 0.00130 AC: 58 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000764 AC: 85 AN: 1111982

Other (OTH) AF: 0.00156 AC: 94 AN: 60390

GnomAD4 genome AF: 0.00655 AC: 997 AN: 152232 Hom.: 8 Cov.: 32 AF XY: 0.00625 AC XY: 465 AN XY: 74436

African (AFR) AF: 0.0225 AC: 933 AN: 41530

American (AMR) AF: 0.00314 AC: 48 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00244 Hom.: 7

Bravo AF: 0.00743

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00189 AC: 230

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	ALG6-congenital disorder of glycosylation 1C (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.17	N
PhyloP100		2.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.21
Sift	Benign	0.32	T
Sift4G	Benign	0.86	T
Vest4		0.29
MVP		0.78
MPC		0.29
ClinPred		0.0053	T
GERP RS		4.3
Varity_R		0.18
gMVP		0.13
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs61755863; hg19: chr1-63877667;