chr1-1048922-T-C

Position:

• chr1-1048922-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198576.4(AGRN):​c.4161T>C​(p.Thr1387Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,556,060 control chromosomes in the GnomAD database, including 255,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (20796 hom., cov: 27)
  • Exomes 𝑓: 0.57 (234866 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.25

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]

AGRN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-1048922-T-C is Benign according to our data. Variant chr1-1048922-T-C is described in ClinVar as [Benign]. Clinvar id is 128307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.4161T>C	p.Thr1387Thr	synonymous_variant	24/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.4161T>C	p.Thr1387Thr	synonymous_variant	24/36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76215 AN: 151176 Hom.: 20786 Cov.: 27

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.597

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.513

GnomAD3 exomes AF: 0.588 AC: 98515 AN: 167448 Hom.: 30184 AF XY: 0.586 AC XY: 52955 AN XY: 90404

Gnomad AFR exome AF: 0.273

Gnomad AMR exome AF: 0.705

Gnomad ASJ exome AF: 0.564

Gnomad EAS exome AF: 0.820

Gnomad SAS exome AF: 0.559

Gnomad FIN exome AF: 0.542

Gnomad NFE exome AF: 0.565

Gnomad OTH exome AF: 0.572

GnomAD4 exome AF: 0.574 AC: 806482 AN: 1404778 Hom.: 234866 Cov.: 66 AF XY: 0.573 AC XY: 397526 AN XY: 693336

Gnomad4 AFR exome AF: 0.275

Gnomad4 AMR exome AF: 0.694

Gnomad4 ASJ exome AF: 0.564

Gnomad4 EAS exome AF: 0.832

Gnomad4 SAS exome AF: 0.559

Gnomad4 FIN exome AF: 0.542

Gnomad4 NFE exome AF: 0.573

Gnomad4 OTH exome AF: 0.563

GnomAD4 genome AF: 0.504 AC: 76258 AN: 151282 Hom.: 20796 Cov.: 27 AF XY: 0.509 AC XY: 37606 AN XY: 73906

Gnomad4 AFR AF: 0.292

Gnomad4 AMR AF: 0.647

Gnomad4 ASJ AF: 0.566

Gnomad4 EAS AF: 0.818

Gnomad4 SAS AF: 0.567

Gnomad4 FIN AF: 0.538

Gnomad4 NFE AF: 0.562

Gnomad4 OTH AF: 0.517

Alfa AF: 0.552 Hom.: 8268

Bravo AF: 0.503

Asia WGS AF: 0.675 AC: 2344 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
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	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.24
DANN	Benign	0.25

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: rs9442391; hg19: chr1-984302;