1-95064972-T-C

Position:

chr1-95064972-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144988.4(ALG14):c.182A>G(p.Asn61Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000554 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

ALG14
NM_144988.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.0970

Variant links:

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]

ALG14 links:

ALG14-AS1 (HGNC:41192): (ALG14 antisense RNA 1)

ALG14-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009391874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG14	NM_144988.4 linkuse as main transcript	c.182A>G	p.Asn61Ser	missense_variant	2/4	ENST00000370205.6	NP_659425.1
ALG14-AS1	NR_132786.1 linkuse as main transcript	n.595-2072T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ALG14	ENST00000370205.6 linkuse as main transcript	c.182A>G	p.Asn61Ser	missense_variant	2/4	1	NM_144988.4	ENSP00000359224	P1
ALG14-AS1	ENST00000451611.1 linkuse as main transcript	n.595-2072T>C		intron_variant, non_coding_transcript_variant		1
ALG14	ENST00000495856.1 linkuse as main transcript	n.158A>G		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

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:

0.000617

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000422

AC:

106

AN:

250934

Hom.:

AF XY:

0.000413

AC XY:

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.000724

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000600

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000554

AC:

810

AN:

1461548

Hom.:

Cov.:

AF XY:

0.000539

AC XY:

392

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000667

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000552

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000705

Hom.:

Bravo

AF:

0.000570

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000511

AC:

EpiCase

AF:

0.000711

EpiControl

AF:

0.000593

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	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2022	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 61 of the ALG14 protein (p.Asn61Ser). This variant is present in population databases (rs138996965, gnomAD 0.07%). 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: 542122). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2024

The c.182A>G (p.N61S) alteration is located in exon 2 (coding exon 2) of the ALG14 gene. This alteration results from a A to G substitution at nucleotide position 182, causing the asparagine (N) at amino acid position 61 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.046

DANN

Benign

0.69

DEOGEN2

Benign

0.20

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.22

M_CAP

Benign

0.011

MetaRNN

Benign

0.0094

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.46

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.63

REVEL

Benign

0.11

Sift

Benign

0.43

Sift4G

Benign

0.71

Polyphen

0.0050

Vest4

0.082

MVP

0.25

MPC

0.29

ClinPred

0.0013

GERP RS

-6.7

Varity_R

0.024

gMVP

0.35

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over