13-36999270-G-A

Variant names:

• chr13-36999270-G-A
• rs147574138
• NM_013338.5:c.31C>T

Variant summary

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

The NM_013338.5(ALG5):​c.31C>T​(p.Leu11Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,224 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L11V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ALG5 NM_013338.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.55
• Publications: 0 publications found

Genes affected

ALG5 (HGNC:20266): (ALG5 dolichyl-phosphate beta-glucosyltransferase) This gene encodes a member of the glycosyltransferase 2 family. The encoded protein participates in glucosylation of the oligomannose core in N-linked glycosylation of proteins. The addition of glucose residues to the oligomannose core is necessary to ensure substrate recognition, and therefore, effectual transfer of the oligomannose core to the nascent glycoproteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

EXOSC8 (HGNC:17035): (exosome component 8) This gene encodes a 3'-5' exoribonuclease that specifically interacts with mRNAs containing AU-rich elements. The encoded protein is part of the exosome complex that is important for the degradation of numerous RNA species. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Mar 2009]

EXOSC8 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia, type 1C

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013338.5. 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
	ALG5	NM_013338.5	MANE Select	c.31C>T	p.Leu11Phe	missense	Exon 1 of 10	NP_037470.1	Q9Y673-1
	ALG5	NM_001142364.1		c.31C>T	p.Leu11Phe	missense	Exon 1 of 9	NP_001135836.1	Q9Y673-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG5	ENST00000239891.4	TSL:1 MANE Select	c.31C>T	p.Leu11Phe	missense	Exon 1 of 10	ENSP00000239891.3	Q9Y673-1
	ALG5	ENST00000857206.1		c.31C>T	p.Leu11Phe	missense	Exon 1 of 11	ENSP00000527265.1
	ALG5	ENST00000857208.1		c.31C>T	p.Leu11Phe	missense	Exon 1 of 10	ENSP00000527267.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428224 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 710402

African (AFR) AF: 0.00 AC: 0 AN: 30310

American (AMR) AF: 0.00 AC: 0 AN: 39962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25250

East Asian (EAS) AF: 0.00 AC: 0 AN: 34992

South Asian (SAS) AF: 0.00 AC: 0 AN: 82784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098296

Other (OTH) AF: 0.0000170 AC: 1 AN: 58974

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.088
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.13	N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T
Sift4G	Benign	0.19	T
Polyphen		0.94	P
Vest4		0.49
MutPred		0.35		Gain of catalytic residue at G12 (P = 6e-04)
MVP		0.86
MPC		0.45
ClinPred		0.75	D
GERP RS		3.6
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.82
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: rs147574138; hg19: chr13-37573407;