rs1349882228

Variant names:

• chr22-33604473-C-T
• rs1349882228
• NM_133642.5:c.577G>A

Variant summary

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

The NM_133642.5(LARGE1):​c.577G>A​(p.Ala193Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: LARGE1 NM_133642.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79

Genes affected

LARGE1 (HGNC:6511): (LARGE xylosyl- and glucuronyltransferase 1) This gene encodes a member of the N-acetylglucosaminyltransferase gene family. It encodes a glycosyltransferase which participates in glycosylation of alpha-dystroglycan, and may carry out the synthesis of glycoprotein and glycosphingolipid sugar chains. It may also be involved in the addition of a repeated disaccharide unit. The protein encoded by this gene is the glycotransferase that adds the final xylose and glucuronic acid to alpha-dystroglycan and thereby allows alpha-dystroglycan to bind ligands including laminin 211 and neurexin. Mutations in this gene cause several forms of congenital muscular dystrophy characterized by cognitive disability and abnormal glycosylation of alpha-dystroglycan. Alternative splicing of this gene results in multiple transcript variants that encode the same protein. [provided by RefSeq, May 2018]

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
LARGE1	NM_133642.5	c.577G>A	p.Ala193Thr	missense_variant	Exon 5 of 15	ENST00000397394.8	NP_598397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8	c.577G>A	p.Ala193Thr	missense_variant	Exon 5 of 15	5	NM_133642.5	ENSP00000380549.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251244 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135776

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy type B6 Uncertain:1

Jun 05, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with threonine at codon 193 of the LARGE11 protein (p.Ala193Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a LARGE11-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on LARGE11 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.62	T;T;T
Polyphen		0.59	P;P;P
Vest4		0.73
MutPred		0.43		Gain of glycosylation at A193 (P = 0.0402);Gain of glycosylation at A193 (P = 0.0402);Gain of glycosylation at A193 (P = 0.0402);
MVP		0.093
MPC		0.96
ClinPred		0.84	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.70

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: rs1349882228; hg19: chr22-34000459;