rs987640

Variant names:

• chr22-33163522-T-A
• rs987640
• ENST00000610186.6:c.*3241A>T

Your query was ambiguous. Multiple possible variants found:

• chr22-33163522-T-A
• chr22-33163522-T-C
• chr22-33163522-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000674562.1(LARGE1):​n.1154A>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 152,062 control chromosomes in the GnomAD database, including 16,556 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (16556 hom., cov: 33)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: LARGE1 ENST00000674562.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0600
• Publications: 15 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 (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000674562.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LARGE1	ENST00000610186.6	TSL:5	c.*3241A>T		3_prime_UTR	Exon 13 of 13	ENSP00000476364.2	V9GY39
	LARGE1	ENST00000608642.6	TSL:5	c.*3241A>T		3_prime_UTR	Exon 12 of 12	ENSP00000476866.2	V9GYK8
	LARGE1	ENST00000609799.6	TSL:5	c.*3241A>T		3_prime_UTR	Exon 11 of 11	ENSP00000476415.2	V9GY56

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70614 AN: 151940 Hom.: 16547 Cov.: 33

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.451

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 2 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.465 AC: 70663 AN: 152058 Hom.: 16556 Cov.: 33 AF XY: 0.467 AC XY: 34737 AN XY: 74314

African (AFR) AF: 0.449 AC: 18642 AN: 41480

American (AMR) AF: 0.457 AC: 6979 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1421 AN: 3468

East Asian (EAS) AF: 0.474 AC: 2456 AN: 5180

South Asian (SAS) AF: 0.689 AC: 3321 AN: 4820

European-Finnish (FIN) AF: 0.472 AC: 4976 AN: 10552

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.459 AC: 31190 AN: 67964

Other (OTH) AF: 0.451 AC: 953 AN: 2112

Alfa AF: 0.308 Hom.: 747

Bravo AF: 0.460

Asia WGS AF: 0.594 AC: 2064 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.55
DANN	Benign	0.71
PhyloP100		-0.060

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs987640;

hg19: chr22-33559508;