22-33316116-C-T

Variant names:

• chr22-33316116-C-T
• rs150861748
• NM_133642.5:c.1420G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_133642.5(LARGE1):​c.1420G>A​(p.Val474Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00164 in 1,613,966 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V474F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (6 hom.)
• Consequence: LARGE1 NM_133642.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10 B:1
• Conservation: PhyloP100: 5.68
• Publications: 7 publications found

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]

LARGE1 Gene-Disease associations (from GenCC):

• muscular dystrophy-dystroglycanopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy type B6

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026062876).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00116 (176/152256) while in subpopulation NFE AF = 0.00209 (142/68016). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133642.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	NM_133642.5	MANE Select	c.1420G>A	p.Val474Ile	missense	Exon 11 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.1420G>A	p.Val474Ile	missense	Exon 12 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.1420G>A	p.Val474Ile	missense	Exon 11 of 15	NP_001349880.1	O95461-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	ENST00000397394.8	TSL:5 MANE Select	c.1420G>A	p.Val474Ile	missense	Exon 11 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.1420G>A	p.Val474Ile	missense	Exon 12 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.1264G>A	p.Val422Ile	missense	Exon 10 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000844 AC: 212 AN: 251048 AF XY: 0.000744

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00169 AC: 2477 AN: 1461710 Hom.: 6 Cov.: 31 AF XY: 0.00158 AC XY: 1149 AN XY: 727152

African (AFR) AF: 0.000358 AC: 12 AN: 33474

American (AMR) AF: 0.000380 AC: 17 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86236

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53396

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00206 AC: 2292 AN: 1111924

Other (OTH) AF: 0.00182 AC: 110 AN: 60376

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74434

African (AFR) AF: 0.000385 AC: 16 AN: 41550

American (AMR) AF: 0.000719 AC: 11 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00209 AC: 142 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00158 Hom.: 1

Bravo AF: 0.00112

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.000865 AC: 105

EpiCase AF: 0.00185

EpiControl AF: 0.00136

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	2	-	Muscular dystrophy-dystroglycanopathy type B6 (2)
-	2	-	not specified (2)
-	-	1	LARGE1-related disorder (1)
-	1	-	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (1)
-	1	-	Muscular dystrophy-dystroglycanopathy type B6;C3150414:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.083
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.88	T
PhyloP100		5.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.091
Sift	Benign	0.17	T
Sift4G	Benign	0.18	T
Polyphen		0.54	P
Vest4		0.47
MVP		0.093
MPC		0.48
ClinPred		0.024	T
GERP RS		4.3
Varity_R		0.12
gMVP		0.38
Mutation Taster		=55/45	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

dbSNP: rs150861748; hg19: chr22-33712102; COSMIC: COSV99047006; COSMIC: COSV99047006;