22-33277139-C-T

Variant names:

• chr22-33277139-C-T
• rs1046166
• NM_133642.5:c.1994G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_133642.5(LARGE1):​c.1994G>A​(p.Arg665His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00929 in 1,614,246 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts 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. R665C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (96 hom.)
• Consequence: LARGE1 NM_133642.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.91
• Publications: 11 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 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=0.008549035).
• BP6: Variant 22-33277139-C-T is Benign according to our data. Variant chr22-33277139-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00597 (910/152376) while in subpopulation NFE AF = 0.00992 (675/68034). AF 95% confidence interval is 0.0093. There are 5 homozygotes in GnomAd4. There are 386 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.1994G>A	p.Arg665His	missense	Exon 14 of 15	NP_598397.1
	LARGE1	NM_001362949.2		c.1994G>A	p.Arg665His	missense	Exon 15 of 16	NP_001349878.1
	LARGE1	NM_001362951.2		c.1994G>A	p.Arg665His	missense	Exon 14 of 15	NP_001349880.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	ENST00000397394.8	TSL:5 MANE Select	c.1994G>A	p.Arg665His	missense	Exon 14 of 15	ENSP00000380549.2
	LARGE1	ENST00000354992.7	TSL:1	c.1994G>A	p.Arg665His	missense	Exon 15 of 16	ENSP00000347088.2
	LARGE1	ENST00000402320.6	TSL:1	c.1838G>A	p.Arg613His	missense	Exon 13 of 14	ENSP00000385223.1

Frequencies

GnomAD3 genomes AF: 0.00598 AC: 910 AN: 152258 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00992

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00527 AC: 1324 AN: 251412 AF XY: 0.00553

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00915

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00964 AC: 14086 AN: 1461870 Hom.: 96 Cov.: 32 AF XY: 0.00932 AC XY: 6775 AN XY: 727232

African (AFR) AF: 0.00188 AC: 63 AN: 33480

American (AMR) AF: 0.00293 AC: 131 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00373 AC: 322 AN: 86258

European-Finnish (FIN) AF: 0.00198 AC: 106 AN: 53420

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0117 AC: 13063 AN: 1111990

Other (OTH) AF: 0.00632 AC: 382 AN: 60396

GnomAD4 genome AF: 0.00597 AC: 910 AN: 152376 Hom.: 5 Cov.: 32 AF XY: 0.00518 AC XY: 386 AN XY: 74524

African (AFR) AF: 0.00228 AC: 95 AN: 41594

American (AMR) AF: 0.00215 AC: 33 AN: 15314

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4832

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00992 AC: 675 AN: 68034

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00817 Hom.: 38

Bravo AF: 0.00615

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0108 AC: 93

ExAC AF: 0.00503 AC: 611

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00840

EpiControl AF: 0.00883

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Muscular dystrophy-dystroglycanopathy type B6 (2)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.79	T
PhyloP100		2.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.49
MVP		0.48
MPC		1.6
ClinPred		0.023	T
GERP RS		3.4
Varity_R		0.41
gMVP		0.71
Mutation Taster		=95/5	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: rs1046166; hg19: chr22-33673125;