rs1555452127

Positions:

• chr16-5079078-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_019109.5(ALG1):​c.877T>C​(p.Ser293Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALG1 NM_019109.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.30

Genes affected

ALG1 (HGNC:18294): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase) The enzyme encoded by this gene catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides. This gene is mutated in congenital disorder of glycosylation type Ik. [provided by RefSeq, Dec 2008]

ALG1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• PP5: Variant 16-5079078-T-C is Pathogenic according to our data. Variant chr16-5079078-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522808.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG1	NM_019109.5	c.877T>C	p.Ser293Pro	missense_variant	8/13	ENST00000262374.10	NP_061982.3
ALG1	NM_001330504.2	c.544T>C	p.Ser182Pro	missense_variant	8/13		NP_001317433.1
ALG1	XM_017023457.3	c.862+200T>C		intron_variant			XP_016878946.1
ALG1	XR_007064892.1	n.884T>C		non_coding_transcript_exon_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG1	ENST00000262374.10	c.877T>C	p.Ser293Pro	missense_variant	8/13	1	NM_019109.5	ENSP00000262374.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

ALG1-congenital disorder of glycosylation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Jun 23, 2017

Clinical genome sequencing revealed 3 variants of uncertain significance in the ALG1 gene. Multiple lines of computational evidence support a deleterious effect of these variants on the gene or gene product. cDNA experiments performed on a research basis demonstrated that the paternally inherited variant (c.1187+3A>G) is damaging. The maternally inherited variants are rare and are not present in the 1000 Genomes Project nor the Exome Aggregate Consortium (ExAC) databases. Based on these findings, the clinical team elevated these variants to likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;D;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	.;T;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.6	.;H;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.5	.;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.016	.;D;D
Sift4G	Uncertain	0.042	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.82
MutPred		0.60		.;Loss of phosphorylation at S293 (P = 0.0601);.;
MVP		0.93
MPC		0.16
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555452127; hg19: chr16-5129079;