NM_001004127.3:c.836A>C

Variant names:

• chr13-52024566-A-C
• rs387907181
• NM_001004127.3:c.836A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001004127.3(ALG11):​c.836A>C​(p.Tyr279Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,868 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ALG11 NM_001004127.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.89
• Publications: 7 publications found

Genes affected

ALG11 (HGNC:32456): (ALG11 alpha-1,2-mannosyltransferase) This gene encodes a GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase which is localized to the cytosolic side of the endoplasmic reticulum (ER) and catalyzes the transfer of the fourth and fifth mannose residue from GDP-mannose (GDP-Man) to Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol resulting in the production of Man5GlcNAc2-PP-dolichol. Mutations in this gene are associated with congenital disorder of glycosylation type Ip (CDGIP). This gene overlaps but is distinct from the UTP14, U3 small nucleolar ribonucleoprotein, homolog C (yeast) gene. A pseudogene of the GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase has been identified on chromosome 19. [provided by RefSeq, Aug 2010]

UTP14C (HGNC:20321): (UTP14C small subunit processome component) Predicted to be involved in several processes, including meiotic cell cycle; rRNA processing; and spermatogenesis. Located in cytosol and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 144) in uniprot entity ALG11_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001004127.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 13-52024566-A-C is Pathogenic according to our data. Variant chr13-52024566-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31644.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG11	NM_001004127.3	c.836A>C	p.Tyr279Ser	missense_variant	Exon 3 of 4	ENST00000521508.2	NP_001004127.2
ALG11	NR_036571.3	n.66-3753A>C		intron_variant	Intron 1 of 1
UTP14C	NM_021645.6	c.-858A>C		upstream_gene_variant		ENST00000521776.2	NP_067677.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG11	ENST00000521508.2	c.836A>C	p.Tyr279Ser	missense_variant	Exon 3 of 4	1	NM_001004127.3	ENSP00000430236.1
UTP14C	ENST00000521776.2	c.-858A>C		upstream_gene_variant		1	NM_021645.6	ENSP00000428619.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000716 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

ALG11-congenital disorder of glycosylation Pathogenic:1

Mar 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

ALG11-related disorder Pathogenic:1

Jul 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ALG11 c.836A>C variant is predicted to result in the amino acid substitution p.Tyr279Ser. This variant was reported in the compound heterozygous state with a pathogenic variant in an individual with congenital disorder of glycosylation 1p (Thiel et al. 2012. PubMed ID: 22213132). Analysis of the patient's fibroblasts revealed normal mRNA levels and reduced ALG11 protein level to about 20% of the controls (Sakson et al. 2024. PubMed ID: 38256263). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		8.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.65		Gain of catalytic residue at P281 (P = 2e-04);
MVP		0.97
MPC		0.34
ClinPred		1.0	D
GERP RS		6.0
PromoterAI		-0.0027	Neutral
Varity_R		0.93
gMVP		0.93
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs387907181; hg19: chr13-52598702;