chr1-1047403-T-C

Position:

• chr1-1047403-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198576.4(AGRN):​c.3465T>C​(p.Ala1155=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,612,498 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (5 hom., cov: 34)
  • Exomes 𝑓: 0.0058 (28 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -5.04

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-1047403-T-C is Benign according to our data. Variant chr1-1047403-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00648 (987/152322) while in subpopulation AFR AF= 0.00972 (404/41578). AF 95% confidence interval is 0.00894. There are 5 homozygotes in gnomad4. There are 466 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.3465T>C	p.Ala1155=	synonymous_variant	20/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.3465T>C	p.Ala1155=	synonymous_variant	20/36	1	NM_198576.4	ENSP00000368678	P1

Frequencies

GnomAD3 genomes AF: 0.00645 AC: 982 AN: 152204 Hom.: 5 Cov.: 34

Gnomad AFR AF: 0.00962

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.000658

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00692

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00480 AC: 1200 AN: 250022 Hom.: 2 AF XY: 0.00471 AC XY: 638 AN XY: 135500

Gnomad AFR exome AF: 0.00941

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.000501

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00222

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00736

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00584 AC: 8529 AN: 1460176 Hom.: 28 Cov.: 32 AF XY: 0.00575 AC XY: 4175 AN XY: 726312

Gnomad4 AFR exome AF: 0.00965

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00298

Gnomad4 FIN exome AF: 0.00136

Gnomad4 NFE exome AF: 0.00665

Gnomad4 OTH exome AF: 0.00499

GnomAD4 genome AF: 0.00648 AC: 987 AN: 152322 Hom.: 5 Cov.: 34 AF XY: 0.00626 AC XY: 466 AN XY: 74486

Gnomad4 AFR AF: 0.00972

Gnomad4 AMR AF: 0.00398

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.000658

Gnomad4 NFE AF: 0.00693

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00508 Hom.: 0

Bravo AF: 0.00696

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00919

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	AGRN: BP4, BP7, BS2 -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.18
DANN	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs146358566; hg19: chr1-982783; COSMIC: COSV65070060; COSMIC: COSV65070060;