chr5-179798580-C-T

Variant names:

• chr5-179798580-C-T
• rs751247174
• NM_014275.5:c.1355G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014275.5(MGAT4B):​c.1355G>A​(p.Arg452His) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MGAT4B NM_014275.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

Genes affected

MGAT4B (HGNC:7048): (alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase B) This gene encodes a key glycosyltransferase that regulates the formation of tri- and multiantennary branching structures in the Golgi apparatus. The encoded protein, in addition to the related isoenzyme A, catalyzes the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc in a beta-1,4 linkage to the Man-alpha-1,3-Man-beta-1,4-GlcNAc arm of R-Man-alpha-1,6(GlcNAc-beta-1,2-Man-alpha-1,3)Man-beta-1,4-GlcNAc-beta-1,4-GlcNAc-beta-1-Asn. The encoded protein may play a role in regulating the availability of serum glycoproteins, oncogenesis, and differentiation. [provided by RefSeq, Jul 2008]

MIR1229 (HGNC:33924): (microRNA 1229) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGAT4B	NM_014275.5	c.1355G>A	p.Arg452His	missense_variant	Exon 12 of 15	ENST00000292591.12	NP_055090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGAT4B	ENST00000292591.12	c.1355G>A	p.Arg452His	missense_variant	Exon 12 of 15	1	NM_014275.5	ENSP00000292591.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250740 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461086 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 726836

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1400G>A (p.R467H) alteration is located in exon 11 (coding exon 11) of the MGAT4B gene. This alteration results from a G to A substitution at nucleotide position 1400, causing the arginine (R) at amino acid position 467 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	.;L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.38
Sift	Benign	0.20	T;T
Sift4G	Benign	0.12	T;T
Polyphen		1.0	.;D
Vest4		0.58
MutPred		0.37		.;Gain of glycosylation at S453 (P = 0.0722);
MVP		0.32
MPC		0.64
ClinPred		0.94	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs751247174; hg19: chr5-179225580; COSMIC: COSV99482334; COSMIC: COSV99482334;