rs41285372

Variant names:

• chr1-63436853-C-G
• rs41285372
• NM_013339.4:c.1357C>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.1357C>G​(p.Leu453Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,613,650 control chromosomes in the GnomAD database, including 327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L453L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 32)
  • Exomes 𝑓: 0.018 (305 hom.)
• Consequence: ALG6 NM_013339.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.67
• Publications: 7 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=0.009320587).
• BP6: Variant 1-63436853-C-G is Benign according to our data. Variant chr1-63436853-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 380085.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 = 0.0125 (1902/152172) while in subpopulation NFE AF = 0.0201 (1366/67984). AF 95% confidence interval is 0.0192. There are 22 homozygotes in GnomAd4. There are 897 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.1357C>G	p.Leu453Val	missense	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.1357C>G	p.Leu453Val	missense	Exon 15 of 15	ENSP00000263440.5	Q9Y672
	ALG6	ENST00000948329.1		c.1357C>G	p.Leu453Val	missense	Exon 15 of 15	ENSP00000618388.1
	ALG6	ENST00000920026.1		c.1342C>G	p.Leu448Val	missense	Exon 15 of 15	ENSP00000590085.1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1903 AN: 152054 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00845

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0121 AC: 3029 AN: 251010 AF XY: 0.0122

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00578

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.0188

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0180 AC: 26318 AN: 1461478 Hom.: 305 Cov.: 31 AF XY: 0.0174 AC XY: 12683 AN XY: 727042

African (AFR) AF: 0.00287 AC: 96 AN: 33468

American (AMR) AF: 0.00686 AC: 307 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 374 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00419 AC: 361 AN: 86254

European-Finnish (FIN) AF: 0.0137 AC: 733 AN: 53408

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.0211 AC: 23500 AN: 1111672

Other (OTH) AF: 0.0152 AC: 918 AN: 60384

GnomAD4 genome AF: 0.0125 AC: 1902 AN: 152172 Hom.: 22 Cov.: 32 AF XY: 0.0121 AC XY: 897 AN XY: 74384

African (AFR) AF: 0.00274 AC: 114 AN: 41542

American (AMR) AF: 0.00837 AC: 128 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4822

European-Finnish (FIN) AF: 0.0160 AC: 169 AN: 10580

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

European-Non Finnish (NFE) AF: 0.0201 AC: 1366 AN: 67984

Other (OTH) AF: 0.0119 AC: 25 AN: 2106

Alfa AF: 0.0177 Hom.: 24

Bravo AF: 0.0119

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0254 AC: 98

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0177 AC: 152

ExAC AF: 0.0121 AC: 1466

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0194

EpiControl AF: 0.0192

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.096	T
Vest4		0.36
MPC		0.98
ClinPred		0.014	T
GERP RS		3.2
Varity_R		0.48
gMVP		0.46
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs41285372; hg19: chr1-63902524;