chr13-36965725-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_013338.5(ALG5):​c.623G>A​(p.Arg208His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,606,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ALG5
NM_013338.5 missense, splice_region

Scores

12
5
2
Splicing: ADA: 0.9840
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.68
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
Variant 13-36965725-C-T is Pathogenic according to our data. Variant chr13-36965725-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1708164.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ALG5NM_013338.5 linkuse as main transcriptc.623G>A p.Arg208His missense_variant, splice_region_variant 8/10 ENST00000239891.4
ALG5NM_001142364.1 linkuse as main transcriptc.533G>A p.Arg178His missense_variant, splice_region_variant 7/9
ALG5XM_047430283.1 linkuse as main transcriptc.434G>A p.Arg145His missense_variant, splice_region_variant 6/8
ALG5XR_007063678.1 linkuse as main transcriptn.799G>A splice_region_variant, non_coding_transcript_exon_variant 9/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ALG5ENST00000239891.4 linkuse as main transcriptc.623G>A p.Arg208His missense_variant, splice_region_variant 8/101 NM_013338.5 P1Q9Y673-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152120
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000411
AC:
1
AN:
243508
Hom.:
0
AF XY:
0.00000758
AC XY:
1
AN XY:
131988
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000338
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1454446
Hom.:
0
Cov.:
30
AF XY:
0.00000276
AC XY:
2
AN XY:
723740
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152120
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Polycystic kidney disease 7 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 04, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.67
.;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.075
D
MetaRNN
Pathogenic
0.84
D;D
MetaSVM
Uncertain
0.38
D
MutationAssessor
Pathogenic
3.9
.;H
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-5.0
D;D
REVEL
Uncertain
0.54
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.014
D;D
Polyphen
1.0
D;D
Vest4
0.94
MutPred
0.68
.;Gain of catalytic residue at R212 (P = 0.0044);
MVP
0.91
MPC
1.2
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.79
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Pathogenic
0.90
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs749484470; hg19: chr13-37539862; COSMIC: COSV99523526; API