NM_133642.5:c.1949G>A

Variant names:

• chr22-33277184-C-T
• rs73399520
• NM_133642.5:c.1949G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133642.5(LARGE1):​c.1949G>A​(p.Arg650Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,614,220 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R650W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (78 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (74 hom.)
• Consequence: LARGE1 NM_133642.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.15
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042630434).
• BP6: Variant 22-33277184-C-T is Benign according to our data. Variant chr22-33277184-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

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.1949G>A	p.Arg650Gln	missense	Exon 14 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.1949G>A	p.Arg650Gln	missense	Exon 15 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.1949G>A	p.Arg650Gln	missense	Exon 14 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.1949G>A	p.Arg650Gln	missense	Exon 14 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.1949G>A	p.Arg650Gln	missense	Exon 15 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.1793G>A	p.Arg598Gln	missense	Exon 13 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2631 AN: 152220 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0606

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00490 AC: 1231 AN: 251342 AF XY: 0.00330

Gnomad AFR exome AF: 0.0613

Gnomad AMR exome AF: 0.00541

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00176 AC: 2574 AN: 1461882 Hom.: 74 Cov.: 32 AF XY: 0.00145 AC XY: 1058 AN XY: 727244

African (AFR) AF: 0.0602 AC: 2017 AN: 33478

American (AMR) AF: 0.00537 AC: 240 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1112006

Other (OTH) AF: 0.00396 AC: 239 AN: 60396

GnomAD4 genome AF: 0.0173 AC: 2631 AN: 152338 Hom.: 78 Cov.: 32 AF XY: 0.0158 AC XY: 1177 AN XY: 74488

African (AFR) AF: 0.0604 AC: 2513 AN: 41576

American (AMR) AF: 0.00536 AC: 82 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68028

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00805 Hom.: 20

Bravo AF: 0.0199

ESP6500AA AF: 0.0601 AC: 265

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00605 AC: 735

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Muscular dystrophy-dystroglycanopathy type B6 (2)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.049
Sift	Benign	0.40	T
Sift4G	Benign	0.49	T
Polyphen		0.083	B
Vest4		0.16
MVP		0.043
MPC		0.60
ClinPred		0.0089	T
GERP RS		3.0
Varity_R		0.047
gMVP		0.55
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs73399520; hg19: chr22-33673170;