rs147346337

chr1-1043288-G-A

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.1434G>A(p.Thr478=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,611,818 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (24 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.67

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=-0.87).
• BP6: Variant 1-1043288-G-A is Benign according to our data. Variant chr1-1043288-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1043288-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00276 (420/152320) while in subpopulation NFE AF= 0.00443 (301/68018). AF 95% confidence interval is 0.00401. There are 1 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.1434G>A	p.Thr478=	synonymous_variant	8/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.1434G>A	p.Thr478=	synonymous_variant	8/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.1119G>A	p.Thr373=	synonymous_variant	7/38
AGRN	ENST00000652369.1	c.1119G>A	p.Thr373=	synonymous_variant	7/35
AGRN	ENST00000620552.4	c.1020G>A	p.Thr340=	synonymous_variant	8/39	5

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 420 AN: 152202 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00442

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00272 AC: 667 AN: 244910 Hom.: 3 AF XY: 0.00283 AC XY: 376 AN XY: 132768

Gnomad AFR exome AF: 0.000698

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.000388

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00420 AC: 6126 AN: 1459498 Hom.: 24 Cov.: 35 AF XY: 0.00408 AC XY: 2961 AN XY: 725914

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00178

Gnomad4 FIN exome AF: 0.000438

Gnomad4 NFE exome AF: 0.00468

Gnomad4 OTH exome AF: 0.00592

GnomAD4 genome AF: 0.00276 AC: 420 AN: 152320 Hom.: 1 Cov.: 33 AF XY: 0.00238 AC XY: 177 AN XY: 74480

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00443

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00414 Hom.: 1

Bravo AF: 0.00287

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	AGRN: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.22
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs147346337; hg19: chr1-978668; COSMIC: COSV65069060; COSMIC: COSV65069060;