14-49620844-C-T

Variant names:

• chr14-49620844-C-T
• rs762760581
• NM_002408.4:c.-425C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_002408.4(MGAT2):​c.-425C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 635,670 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: MGAT2 NM_002408.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.748

Genes affected

MGAT2 (HGNC:7045): (alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase) The product of this gene is a Golgi enzyme catalyzing an essential step in the conversion of oligomannose to complex N-glycans. The enzyme has the typical glycosyltransferase domains: a short N-terminal cytoplasmic domain, a hydrophobic non-cleavable signal-anchor domain, and a C-terminal catalytic domain. Mutations in this gene may lead to carbohydrate-deficient glycoprotein syndrome, type II. The coding region of this gene is intronless. Transcript variants with a spliced 5' UTR may exist, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ENSG00000258377 (HGNC:):

RPL36AL (HGNC:10346): (ribosomal protein L36a like) Cytoplasmic ribosomes, organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein, which shares sequence similarity with yeast ribosomal protein L44, belongs to the L44E (L36AE) family of ribosomal proteins. This gene and the human gene officially named ribosomal protein L36a (RPL36A) encode nearly identical proteins; however, they are distinct genes. Although the name of this gene has been referred to as ribosomal protein L36a (RPL36A), its official name is ribosomal protein L36a-like (RPL36AL). As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000341 (52/152350) while in subpopulation AMR AF= 0.000261 (4/15314). AF 95% confidence interval is 0.000159. There are 1 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGAT2	NM_002408.4	c.-425C>T		5_prime_UTR_variant	Exon 1 of 1	ENST00000305386.4	NP_002399.1
RPL36AL	NM_001001.5	c.-319G>A		upstream_gene_variant		ENST00000298289.7	NP_000992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGAT2	ENST00000305386	c.-425C>T		5_prime_UTR_variant	Exon 1 of 1		NM_002408.4	ENSP00000307423.2
ENSG00000258377	ENST00000555043.1	n.2440G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
RPL36AL	ENST00000298289.7	c.-319G>A		upstream_gene_variant		1	NM_001001.5	ENSP00000346012.5

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152232 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000468 AC: 226 AN: 483320 Hom.: 1 Cov.: 0 AF XY: 0.000512 AC XY: 133 AN XY: 259708

Gnomad4 AFR exome AF: 0.000156

Gnomad4 AMR exome AF: 0.000170

Gnomad4 ASJ exome AF: 0.00778

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000934

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000234

Gnomad4 OTH exome AF: 0.00102

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152350 Hom.: 1 Cov.: 34 AF XY: 0.000282 AC XY: 21 AN XY: 74504

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000370

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MGAT2-congenital disorder of glycosylation Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.7
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Other links and lift over

dbSNP: rs762760581; hg19: chr14-50087562;