1-95064960-G-A

Variant names:

• chr1-95064960-G-A
• rs730882050
• NM_144988.4:c.194C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_144988.4(ALG14):​c.194C>T​(p.Pro65Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALG14 NM_144988.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.70
• Publications: 5 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]

CNN3-DT (HGNC:54176): (CNN3 divergent transcript)

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 1-95064960-G-A is Pathogenic according to our data. Variant chr1-95064960-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 183013.Status of the report is no_assertion_criteria_provided, 0 stars.

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.194C>T	p.Pro65Leu	missense	Exon 2 of 4	NP_659425.1
	ALG14	NM_001305242.2		c.194C>T	p.Pro65Leu	missense	Exon 2 of 5	NP_001292171.1
	ALG14	NR_131032.2		n.189+7803C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG14	ENST00000370205.6	TSL:1 MANE Select	c.194C>T	p.Pro65Leu	missense	Exon 2 of 4	ENSP00000359224.4
	ALG14	ENST00000495856.1	TSL:3	n.170C>T		non_coding_transcript_exon	Exon 2 of 4
	CNN3-DT	ENST00000715651.1		n.1005-2084G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461456 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727032

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111718

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital myasthenic syndrome 15 Pathogenic:1

Mar 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.80	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		6.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-9.1	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.95	P
Vest4		0.85
MutPred		0.70		Gain of sheet (P = 0.0266)
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.86
Mutation Taster		=19/81	disease causing (ClinVar)

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: rs730882050; hg19: chr1-95530516;