rs41302579

chr22-33277024-G-Achr22-33277024-G-Cchr22-33277024-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_133642.5(LARGE1):c.2073+36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,600,152 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0089 (9 hom., cov: 33)
  • Exomes 𝑓: 0.011 (112 hom.)
• Consequence: LARGE1 NM_133642.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.507

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 22-33277024-G-A is Benign according to our data. Variant chr22-33277024-G-A is described in ClinVar as [Benign]. Clinvar id is 158806.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-33277024-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0089 (1355/152194) while in subpopulation NFE AF= 0.0128 (870/67998). AF 95% confidence interval is 0.0121. There are 9 homozygotes in gnomad4. There are 664 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LARGE1	NM_133642.5	c.2073+36C>T		intron_variant		ENST00000397394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LARGE1	ENST00000397394.8	c.2073+36C>T		intron_variant		5	NM_133642.5	P1

Frequencies

GnomAD3 genomes AF: 0.00889 AC: 1352 AN: 152076 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00904 AC: 2266 AN: 250560 Hom.: 11 AF XY: 0.00928 AC XY: 1257 AN XY: 135506

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00668

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00647

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0110 AC: 15862 AN: 1447958 Hom.: 112 Cov.: 29 AF XY: 0.0109 AC XY: 7856 AN XY: 721128

Gnomad4 AFR exome AF: 0.00202

Gnomad4 AMR exome AF: 0.00709

Gnomad4 ASJ exome AF: 0.0294

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00750

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.0120

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.00890 AC: 1355 AN: 152194 Hom.: 9 Cov.: 33 AF XY: 0.00892 AC XY: 664 AN XY: 74400

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.00161

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0131 Hom.: 3

Bravo AF: 0.00953

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.43
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs41302579; hg19: chr22-33673010;