rs138996965

Variant names:

• chr1-95064972-T-C
• rs138996965
• NM_144988.4:c.182A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N61D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: ALG14 NM_144988.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.0970
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009391874).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG14	NM_144988.4	MANE Select	c.182A>G	p.Asn61Ser	missense	Exon 2 of 4	NP_659425.1	Q96F25
	ALG14	NM_001305242.2		c.182A>G	p.Asn61Ser	missense	Exon 2 of 5	NP_001292171.1
	ALG14	NR_131032.2		n.189+7791A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG14	ENST00000370205.6	TSL:1 MANE Select	c.182A>G	p.Asn61Ser	missense	Exon 2 of 4	ENSP00000359224.4	Q96F25
	ALG14	ENST00000897799.1		c.182A>G	p.Asn61Ser	missense	Exon 2 of 3	ENSP00000567858.1
	ALG14	ENST00000495856.1	TSL:3	n.158A>G		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152146 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000422 AC: 106 AN: 250934 AF XY: 0.000413

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 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.: 0 Cov.: 31 AF XY: 0.000539 AC XY: 392 AN XY: 727066

African (AFR) AF: 0.000329 AC: 11 AN: 33474

American (AMR) AF: 0.000895 AC: 40 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86222

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000667 AC: 742 AN: 1111806

Other (OTH) AF: 0.000232 AC: 14 AN: 60364

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74452

African (AFR) AF: 0.000866 AC: 36 AN: 41548

American (AMR) AF: 0.000327 AC: 5 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000699 Hom.: 0

Bravo AF: 0.000570

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.000711

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Congenital myasthenic syndrome 15 (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual developmental disorder with epilepsy, behavioral abnormalities, and coarse facies (1)
-	1	-	Myopathy, epilepsy, and progressive cerebral atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.046
DANN	Benign	0.69
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.46	N
PhyloP100		0.097
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.11
Sift	Benign	0.43	T
Sift4G	Benign	0.71	T
Polyphen		0.0050	B
Vest4		0.082
MVP		0.25
MPC		0.29
ClinPred		0.0013	T
GERP RS		-6.7
Varity_R		0.024
gMVP		0.35
Mutation Taster		=96/4	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: rs138996965; hg19: chr1-95530528;