chr1-95072813-A-C

Variant names:

• chr1-95072813-A-C
• rs1156822888
• NM_144988.4:c.86T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144988.4(ALG14):​c.86T>G​(p.Met29Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. M29T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALG14 NM_144988.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.857
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 15

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• myopathy, epilepsy, and progressive cerebral atrophy

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital disorder of glycosylation

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043861836).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144988.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG14	NM_144988.4	MANE Select	c.86T>G	p.Met29Arg	missense	Exon 1 of 4	NP_659425.1
	ALG14	NM_001305242.2		c.86T>G	p.Met29Arg	missense	Exon 1 of 5	NP_001292171.1
	ALG14	NR_131032.2		n.139T>G		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG14	ENST00000370205.6	TSL:1 MANE Select	c.86T>G	p.Met29Arg	missense	Exon 1 of 4	ENSP00000359224.4
	ALG14	ENST00000495856.1	TSL:3	n.62T>G		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.035
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.69
DANN	Benign	0.47
DEOGEN2	Benign	0.061	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.086	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.86
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.0090
Sift	Benign	0.42	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.083
MutPred		0.42		Gain of solvent accessibility (P = 0.0078)
MVP		0.048
MPC		0.54
ClinPred		0.060	T
GERP RS		-1.8
PromoterAI		-0.092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.19
gMVP		0.50
Mutation Taster		=90/10	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: rs1156822888; hg19: chr1-95538369;