chr13-52012436-G-T

Variant names:

• chr13-52012436-G-T
• rs1393492365
• NM_001004127.3:c.18G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001004127.3(ALG11):​c.18G>T​(p.Arg6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R6R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ALG11 NM_001004127.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.420
• 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]

ALG11 Gene-Disease associations (from GenCC):

• ALG11-congenital disorder of glycosylation

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12106365).

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.18G>T	p.Arg6Ser	missense	Exon 1 of 4	NP_001004127.2	Q2TAA5
	ALG11	NR_036571.3		n.39G>T		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG11	ENST00000521508.2	TSL:1 MANE Select	c.18G>T	p.Arg6Ser	missense	Exon 1 of 4	ENSP00000430236.1	Q2TAA5
	ALG11	ENST00000649340.2		c.18G>T	p.Arg6Ser	missense	Exon 1 of 4	ENSP00000497184.2	A0A3B3IS90
	ALG11	ENST00000681053.1		c.18G>T	p.Arg6Ser	missense	Exon 1 of 3	ENSP00000505307.1	A0A7P0T8Y4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461734 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727136

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	11
DANN	Benign	0.70
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.42
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.18
Sift	Benign	0.32	T
Sift4G	Benign	0.45	T
Polyphen		0.0080	B
Vest4		0.28
MutPred		0.41		Gain of catalytic residue at A3 (P = 8e-04)
MVP		0.57
MPC		0.049
ClinPred		0.14	T
GERP RS		4.2
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.070
gMVP		0.54
Mutation Taster		=97/3	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: rs1393492365; hg19: chr13-52586572;