1-63370979-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_013339.4(ALG6):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000005 in 1,598,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ALG6 NM_013339.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.17

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_013339.4 (ALG6) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 554144
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-63370979-T-C is Pathogenic according to our data. Variant chr1-63370979-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558047.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG6	NM_013339.4	c.2T>C	p.Met1?	start_lost	2/15	ENST00000263440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG6	ENST00000263440.6	c.2T>C	p.Met1?	start_lost	2/15	5	NM_013339.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000484 AC: 7 AN: 1446584 Hom.: 0 Cov.: 28 AF XY: 0.00000694 AC XY: 5 AN XY: 720712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000637

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

ALG6-congenital disorder of glycosylation 1C Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Apr 25, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	-0.031	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-2.2	N;N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.94
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0216);Gain of catalytic residue at M1 (P = 0.0216);
MVP		0.89
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1387214955; hg19: chr1-63836650;