chr22-33316116-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 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 -12 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.
• 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;