rs140158304

Variant names:

• chr1-63436894-A-T
• rs140158304
• NM_013339.4:c.1398A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_013339.4(ALG6):​c.1398A>T​(p.Leu466Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,613,872 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: ALG6 NM_013339.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.253
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-63436894-A-T is Benign according to our data. Variant chr1-63436894-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 382062.
• BP7: Synonymous conserved (PhyloP=-0.253 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00154 (235/152234) while in subpopulation AFR AF = 0.00541 (225/41556). AF 95% confidence interval is 0.00483. There are 2 homozygotes in GnomAd4. There are 123 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1398A>T	p.Leu466Leu	synonymous	Exon 15 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.1398A>T	p.Leu466Leu	synonymous	Exon 15 of 15	ENSP00000263440.5	Q9Y672
	ALG6	ENST00000948329.1		c.1398A>T	p.Leu466Leu	synonymous	Exon 15 of 15	ENSP00000618388.1
	ALG6	ENST00000920026.1		c.1383A>T	p.Leu461Leu	synonymous	Exon 15 of 15	ENSP00000590085.1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152116 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00541

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000355 AC: 89 AN: 250964 AF XY: 0.000243

Gnomad AFR exome AF: 0.00505

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000158 AC: 231 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.000143 AC XY: 104 AN XY: 727126

African (AFR) AF: 0.00607 AC: 203 AN: 33466

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

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

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111816

Other (OTH) AF: 0.000282 AC: 17 AN: 60386

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152234 Hom.: 2 Cov.: 32 AF XY: 0.00165 AC XY: 123 AN XY: 74428

African (AFR) AF: 0.00541 AC: 225 AN: 41556

American (AMR) AF: 0.000392 AC: 6 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000625 Hom.: 0

Bravo AF: 0.00182

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	ALG6-congenital disorder of glycosylation 1C (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.4
DANN	Benign	0.83
PhyloP100		-0.25
Mutation Taster		=99/1	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: rs140158304; hg19: chr1-63902565;