22-33382042-A-T

Variant names:

• chr22-33382042-A-T
• rs115076367
• NM_133642.5:c.1008T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_133642.5(LARGE1):​c.1008T>A​(p.Asp336Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D336D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LARGE1 NM_133642.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.784

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LARGE1	NM_133642.5	c.1008T>A	p.Asp336Glu	missense_variant, splice_region_variant	Exon 9 of 15	ENST00000397394.8	NP_598397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARGE1	ENST00000397394.8	c.1008T>A	p.Asp336Glu	missense_variant, splice_region_variant	Exon 9 of 15	5	NM_133642.5	ENSP00000380549.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251326 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135840

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;.;D;D;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.97	D;D;D;.;D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Benign	-0.67	T
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.9	.;.;.;D;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	.;.;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;D;D;.
Vest4		0.97, 0.97, 0.94
MutPred		0.84		.;.;.;Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);.;
MVP		0.59
MPC		1.4
ClinPred		0.99	D
GERP RS		1.5
Varity_R		0.64
gMVP		0.97

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: rs115076367; hg19: chr22-33778028; COSMIC: COSV61667628;