13-52024804-A-C

Variant names:

• chr13-52024804-A-C
• rs774686733
• NM_001004127.3:c.1074A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001004127.3(ALG11):​c.1074A>C​(p.Arg358Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R358R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ALG11 NM_001004127.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17
• Publications: 0 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: Uncertain_significance. The variant received 4 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004127.3. 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
	ALG11	NM_001004127.3	MANE Select	c.1074A>C	p.Arg358Ser	missense	Exon 3 of 4	NP_001004127.2	Q2TAA5
	UTP14C	NM_021645.6	MANE Select	c.-620A>C		5_prime_UTR	Exon 1 of 2	NP_067677.4
	ALG11	NR_036571.3		n.66-3515A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG11	ENST00000521508.2	TSL:1 MANE Select	c.1074A>C	p.Arg358Ser	missense	Exon 3 of 4	ENSP00000430236.1	Q2TAA5
	UTP14C	ENST00000521776.2	TSL:1 MANE Select	c.-620A>C		5_prime_UTR	Exon 1 of 2	ENSP00000428619.1	Q5TAP6
	ALG11	ENST00000649340.2		c.1074A>C	p.Arg358Ser	missense	Exon 3 of 4	ENSP00000497184.2	A0A3B3IS90

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.0052	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.2
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.98	D
Vest4		0.41
MutPred		0.59		Gain of catalytic residue at N355 (P = 0.0254)
MVP		0.88
MPC		0.099
ClinPred		0.97	D
GERP RS		5.0
PromoterAI		0.018	Neutral
Varity_R		0.39
gMVP		0.71
Mutation Taster		=68/32	polymorphism

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: rs774686733; hg19: chr13-52598940;