chr1-1047561-T-C

Position:

• chr1-1047561-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198576.4(AGRN):​c.3517-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.898 in 1,612,772 control chromosomes in the GnomAD database, including 659,170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (51070 hom., cov: 36)
  • Exomes 𝑓: 0.91 (608100 hom.)
• Consequence: AGRN NM_198576.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005620
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.147

Genes affected

AGRN (HGNC:329): (agrin) This gene encodes one of several proteins that are critical in the development of the neuromuscular junction (NMJ), as identified in mouse knock-out studies. The encoded protein contains several laminin G, Kazal type serine protease inhibitor, and epidermal growth factor domains. Additional post-translational modifications occur to add glycosaminoglycans and disulfide bonds. In one family with congenital myasthenic syndrome affecting limb-girdle muscles, a mutation in this gene was found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-1047561-T-C is Benign according to our data. Variant chr1-1047561-T-C is described in ClinVar as [Benign]. Clinvar id is 263181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1047561-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.3517-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.3517-12T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_198576.4	P1

Frequencies

GnomAD3 genomes AF: 0.794 AC: 120768 AN: 152128 Hom.: 51078 Cov.: 36

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 0.968

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.917

Gnomad OTH AF: 0.830

GnomAD3 exomes AF: 0.896 AC: 223530 AN: 249388 Hom.: 101968 AF XY: 0.904 AC XY: 122506 AN XY: 135498

Gnomad AFR exome AF: 0.447

Gnomad AMR exome AF: 0.932

Gnomad ASJ exome AF: 0.917

Gnomad EAS exome AF: 0.973

Gnomad SAS exome AF: 0.944

Gnomad FIN exome AF: 0.933

Gnomad NFE exome AF: 0.913

Gnomad OTH exome AF: 0.899

GnomAD4 exome AF: 0.909 AC: 1328134 AN: 1460526 Hom.: 608100 Cov.: 63 AF XY: 0.912 AC XY: 662285 AN XY: 726556

Gnomad4 AFR exome AF: 0.439

Gnomad4 AMR exome AF: 0.925

Gnomad4 ASJ exome AF: 0.914

Gnomad4 EAS exome AF: 0.970

Gnomad4 SAS exome AF: 0.943

Gnomad4 FIN exome AF: 0.932

Gnomad4 NFE exome AF: 0.918

Gnomad4 OTH exome AF: 0.890

GnomAD4 genome AF: 0.793 AC: 120782 AN: 152246 Hom.: 51070 Cov.: 36 AF XY: 0.798 AC XY: 59434 AN XY: 74448

Gnomad4 AFR AF: 0.463

Gnomad4 AMR AF: 0.884

Gnomad4 ASJ AF: 0.920

Gnomad4 EAS AF: 0.968

Gnomad4 SAS AF: 0.946

Gnomad4 FIN AF: 0.939

Gnomad4 NFE AF: 0.917

Gnomad4 OTH AF: 0.831

Alfa AF: 0.877 Hom.: 11964

Bravo AF: 0.773

Asia WGS AF: 0.922 AC: 3207 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital myasthenic syndrome 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.1
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000056
dbscSNV1_RF	Benign	0.014
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

Publications

LitVar

Other links and lift over

dbSNP: rs3128102; hg19: chr1-982941;