13-36999270-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_013338.5(ALG5):​c.31C>G​(p.Leu11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,580,554 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: ALG5 NM_013338.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.55
• Publications: 1 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016397238).
• BP6: Variant 13-36999270-G-C is Benign according to our data. Variant chr13-36999270-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3040312.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000807 (123/152328) while in subpopulation NFE AF = 0.00116 (79/68030). AF 95% confidence interval is 0.000955. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 123 AD gene.

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>G	p.Leu11Val	missense	Exon 1 of 10	NP_037470.1	Q9Y673-1
	ALG5	NM_001142364.1		c.31C>G	p.Leu11Val	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>G	p.Leu11Val	missense	Exon 1 of 10	ENSP00000239891.3	Q9Y673-1
	ALG5	ENST00000857206.1		c.31C>G	p.Leu11Val	missense	Exon 1 of 11	ENSP00000527265.1
	ALG5	ENST00000857208.1		c.31C>G	p.Leu11Val	missense	Exon 1 of 10	ENSP00000527267.1

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000998 AC: 207 AN: 207344 AF XY: 0.000996

Gnomad AFR exome AF: 0.000375

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00272

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.000621

GnomAD4 exome AF: 0.00110 AC: 1576 AN: 1428226 Hom.: 1 Cov.: 30 AF XY: 0.00109 AC XY: 776 AN XY: 710402

African (AFR) AF: 0.000165 AC: 5 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: 0.00281 AC: 146 AN: 51984

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

European-Non Finnish (NFE) AF: 0.00124 AC: 1365 AN: 1098298

Other (OTH) AF: 0.00102 AC: 60 AN: 58974

GnomAD4 genome AF: 0.000807 AC: 123 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74478

African (AFR) AF: 0.000289 AC: 12 AN: 41586

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000375 Hom.: 0

Bravo AF: 0.000518

ExAC AF: 0.000995 AC: 120

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ALG5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.21
Sift	Benign	0.050	D
Sift4G	Uncertain	0.047	D
Polyphen		0.015	B
Vest4		0.42
MVP		0.70
MPC		0.42
ClinPred		0.044	T
GERP RS		3.6
PromoterAI		0.056	Neutral
Varity_R		0.10
gMVP		0.82
Mutation Taster		=87/13	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; COSMIC: COSV106089710; COSMIC: COSV106089710;