16-5079078-T-C

Variant names:

• chr16-5079078-T-C
• rs1555452127
• NM_019109.5:c.877T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S293C) has been classified as Uncertain significance.

• 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• ALG1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_019109.5
• 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 VariationId is 522808.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019109.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	NM_019109.5	MANE Select	c.877T>C	p.Ser293Pro	missense	Exon 8 of 13	NP_061982.3
	ALG1	NM_001330504.2		c.544T>C	p.Ser182Pro	missense	Exon 8 of 13	NP_001317433.1
	ALG1	NM_001438123.1		c.862+200T>C		intron	N/A	NP_001425052.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG1	ENST00000262374.10	TSL:1 MANE Select	c.877T>C	p.Ser293Pro	missense	Exon 8 of 13	ENSP00000262374.5
	ALG1	ENST00000588623.5	TSL:1	c.544T>C	p.Ser182Pro	missense	Exon 9 of 14	ENSP00000468118.1
	ALG1	ENST00000591822.5	TSL:1	n.*778T>C		non_coding_transcript_exon	Exon 8 of 13	ENSP00000467865.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	ALG1-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.042	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

Other links and lift over

dbSNP: rs1555452127; hg19: chr16-5129079;