5-179806552-A-C

Variant names:

• chr5-179806552-A-C
• NM_014275.5:c.32T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014275.5(MGAT4B):​c.32T>G​(p.Leu11Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MGAT4B NM_014275.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60
• Publications: 0 publications found

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]

SQSTM1 (HGNC:11280): (sequestosome 1) This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone. [provided by RefSeq, Mar 2009]

SQSTM1 Gene-Disease associations (from GenCC):

• neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Paget disease of bone 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• behavioral variant of frontotemporal dementia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4162677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGAT4B	NM_014275.5	c.32T>G	p.Leu11Arg	missense_variant	Exon 1 of 15	ENST00000292591.12	NP_055090.1
SQSTM1	NM_001142298.2	c.-196A>C		5_prime_UTR_variant	Exon 1 of 9		NP_001135770.1
MGAT4B	XM_024454349.2	c.-4087T>G		upstream_gene_variant			XP_024310117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MGAT4B	ENST00000292591.12	c.32T>G	p.Leu11Arg	missense_variant	Exon 1 of 15	1	NM_014275.5	ENSP00000292591.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1172320 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 577700

African (AFR) AF: 0.00 AC: 0 AN: 22810

American (AMR) AF: 0.00 AC: 0 AN: 23196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17102

East Asian (EAS) AF: 0.00 AC: 0 AN: 17128

South Asian (SAS) AF: 0.00 AC: 0 AN: 64742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4580

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 942566

Other (OTH) AF: 0.00 AC: 0 AN: 43310

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.32T>G (p.L11R) alteration is located in exon 1 (coding exon 1) of the MGAT4B gene. This alteration results from a T to G substitution at nucleotide position 32, causing the leucine (L) at amino acid position 11 to be replaced by an arginine (R). 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	Pathogenic	0.59
BayesDel_addAF	Benign	0.0034	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.0048
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.21
Sift	Benign	0.035	D
Sift4G	Benign	0.11	T
Polyphen		0.64	P
Vest4		0.38
MutPred		0.73		Gain of MoRF binding (P = 0.0022);
MVP		0.35
ClinPred		0.50	T
GERP RS		2.2
PromoterAI		-0.011	Neutral
Varity_R		0.25
Mutation Taster		=80/20	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

hg19: chr5-179233552;