chr22-33761507-C-T

Variant names:

• chr22-33761507-C-T
• rs117199378
• NM_133642.5:c.-31G>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.-31G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,552,466 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (127 hom.)
• Consequence: LARGE1 NM_133642.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.63
• 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 (BayesDel_noAF=-0.8).
• BP6: Variant 22-33761507-C-T is Benign according to our data. Variant chr22-33761507-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0567 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.-31G>A		5_prime_UTR	Exon 2 of 15	NP_598397.1	O95461-1
	LARGE1	NM_001362949.2		c.-31G>A		5_prime_UTR	Exon 3 of 16	NP_001349878.1	O95461-1
	LARGE1	NM_001362951.2		c.-31G>A		5_prime_UTR	Exon 2 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.-31G>A		5_prime_UTR	Exon 2 of 15	ENSP00000380549.2	O95461-1
	LARGE1	ENST00000354992.7	TSL:1	c.-31G>A		5_prime_UTR	Exon 3 of 16	ENSP00000347088.2	O95461-1
	LARGE1	ENST00000402320.6	TSL:1	c.-31G>A		5_prime_UTR	Exon 2 of 14	ENSP00000385223.1	O95461-2

Frequencies

GnomAD3 genomes AF: 0.00728 AC: 1107 AN: 152022 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0600

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0236

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0115 AC: 2870 AN: 250588 AF XY: 0.00932

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.0680

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0249

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.00703

GnomAD4 exome AF: 0.00329 AC: 4602 AN: 1400326 Hom.: 127 Cov.: 23 AF XY: 0.00296 AC XY: 2072 AN XY: 700434

African (AFR) AF: 0.000681 AC: 22 AN: 32282

American (AMR) AF: 0.0655 AC: 2924 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25776

East Asian (EAS) AF: 0.0348 AC: 1371 AN: 39384

South Asian (SAS) AF: 0.000247 AC: 21 AN: 85056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000371 AC: 2 AN: 5388

European-Non Finnish (NFE) AF: 0.0000606 AC: 64 AN: 1056190

Other (OTH) AF: 0.00338 AC: 197 AN: 58252

GnomAD4 genome AF: 0.00726 AC: 1105 AN: 152140 Hom.: 39 Cov.: 32 AF XY: 0.00854 AC XY: 635 AN XY: 74346

African (AFR) AF: 0.000915 AC: 38 AN: 41542

American (AMR) AF: 0.0599 AC: 915 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0237 AC: 121 AN: 5110

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68020

Other (OTH) AF: 0.00995 AC: 21 AN: 2110

Alfa AF: 0.00319 Hom.: 1

Bravo AF: 0.0109

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.6
DANN	Benign	0.86
PhyloP100		-1.6
PromoterAI		0.011	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs117199378; hg19: chr22-34157494;