1-95064975-G-C
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_144988.4(ALG14):āc.179C>Gā(p.Ser60Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,454 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00011 ( 0 hom., cov: 32)
Exomes š: 0.000042 ( 0 hom. )
Consequence
ALG14
NM_144988.4 missense
NM_144988.4 missense
Scores
2
12
5
Clinical Significance
Conservation
PhyloP100: 8.49
Genes affected
ALG14 (HGNC:28287): (ALG14 UDP-N-acetylglucosaminyltransferase subunit) This gene is a member of the glycosyltransferase 1 family. The encoded protein and ALG13 are thought to be subunits of UDP-GlcNAc transferase, which catalyzes the first two committed steps in endoplasmic reticulum N-linked glycosylation. Mutations in this gene have been linked to congenital myasthenic syndrome (CMSWTA). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2015]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALG14 | NM_144988.4 | c.179C>G | p.Ser60Cys | missense_variant | 2/4 | ENST00000370205.6 | |
ALG14-AS1 | NR_132786.1 | n.595-2069G>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALG14 | ENST00000370205.6 | c.179C>G | p.Ser60Cys | missense_variant | 2/4 | 1 | NM_144988.4 | P1 | |
ALG14-AS1 | ENST00000451611.1 | n.595-2069G>C | intron_variant, non_coding_transcript_variant | 1 | |||||
ALG14 | ENST00000495856.1 | n.155C>G | non_coding_transcript_exon_variant | 2/4 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152000Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
16
AN:
152000
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000877 AC: 22AN: 250862Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135566
GnomAD3 exomes
AF:
AC:
22
AN:
250862
Hom.:
AF XY:
AC XY:
9
AN XY:
135566
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461336Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 726934
GnomAD4 exome
AF:
AC:
61
AN:
1461336
Hom.:
Cov.:
31
AF XY:
AC XY:
26
AN XY:
726934
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000105 AC: 16AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74354
GnomAD4 genome
AF:
AC:
16
AN:
152118
Hom.:
Cov.:
32
AF XY:
AC XY:
8
AN XY:
74354
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ExAC
AF:
AC:
10
Asia WGS
AF:
AC:
2
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital myasthenic syndrome 15 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 15, 2022 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 60 of the ALG14 protein (p.Ser60Cys). This variant is present in population databases (rs780277809, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with ALG14-related conditions. ClinVar contains an entry for this variant (Variation ID: 390702). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 15, 2016 | The S60C variant in the ALG14 gene has not been reported previously as a pathogenic variant, nor asa benign variant, to our knowledge. The S60C variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The S60C variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size and/or other properties. This substitution occurs at aposition that is conserved in mammals and in silico analysis predicts this variant is probably damagingto the protein structure/function. A missense variant in nearby residue (P65L) has been reported in the Human Gene Mutation Database in association with congenital myasthenic syndrome (Stenson et al.,2014), supporting the functional importance of this region of the protein. We interpret S60C as avariant of uncertain significance. - |
Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Myopathy, epilepsy, and progressive cerebral atrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of disorder (P = 0.0275);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at