rs113288277

chr1-1044368-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198576.4(AGRN):c.2183A>T(p.Glu728Val) variant causes a missense change. The variant allele was found at a frequency of 0.0373 in 1,612,466 control chromosomes in the GnomAD database, including 1,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E728K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (105 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1191 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.45

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 (MetaRNN=0.0125976205).
• BP6: Variant 1-1044368-A-T is Benign according to our data. Variant chr1-1044368-A-T is described in ClinVar as [Benign]. Clinvar id is 128294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1044368-A-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0294 (4473/151964) while in subpopulation NFE AF= 0.0448 (3044/67948). AF 95% confidence interval is 0.0435. There are 105 homozygotes in gnomad4. There are 2142 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 107 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.2183A>T	p.Glu728Val	missense_variant	12/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.2183A>T	p.Glu728Val	missense_variant	12/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.1868A>T	p.Glu623Val	missense_variant	11/38
AGRN	ENST00000652369.1	c.1868A>T	p.Glu623Val	missense_variant	11/35
AGRN	ENST00000620552.4	c.1769A>T	p.Glu590Val	missense_variant	12/39	5

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4477 AN: 151846 Hom.: 107 Cov.: 33

Gnomad AFR AF: 0.00673

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.00503

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.0388

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0255

GnomAD3 exomes AF: 0.0298 AC: 7415 AN: 249164 Hom.: 152 AF XY: 0.0308 AC XY: 4169 AN XY: 135286

Gnomad AFR exome AF: 0.00636

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0438

Gnomad EAS exome AF: 0.00419

Gnomad SAS exome AF: 0.0221

Gnomad FIN exome AF: 0.0373

Gnomad NFE exome AF: 0.0409

Gnomad OTH exome AF: 0.0339

GnomAD4 exome AF: 0.0381 AC: 55625 AN: 1460502 Hom.: 1191 Cov.: 35 AF XY: 0.0381 AC XY: 27654 AN XY: 726578

Gnomad4 AFR exome AF: 0.00511

Gnomad4 AMR exome AF: 0.0160

Gnomad4 ASJ exome AF: 0.0437

Gnomad4 EAS exome AF: 0.00292

Gnomad4 SAS exome AF: 0.0235

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.0425

Gnomad4 OTH exome AF: 0.0359

GnomAD4 genome AF: 0.0294 AC: 4473 AN: 151964 Hom.: 105 Cov.: 33 AF XY: 0.0288 AC XY: 2142 AN XY: 74314

Gnomad4 AFR AF: 0.00671

Gnomad4 AMR AF: 0.0213

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.00504

Gnomad4 SAS AF: 0.0281

Gnomad4 FIN AF: 0.0388

Gnomad4 NFE AF: 0.0448

Gnomad4 OTH AF: 0.0253

Alfa AF: 0.0395 Hom.: 37

Bravo AF: 0.0269

TwinsUK AF: 0.0340 AC: 126

ALSPAC AF: 0.0322 AC: 124

ESP6500AA AF: 0.00863 AC: 38

ESP6500EA AF: 0.0426 AC: 366

ExAC AF: 0.0292 AC: 3543

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0436

EpiControl AF: 0.0411

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 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. -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Benign	0.23
Sift	Benign	0.036	D;.
Sift4G	Uncertain	0.0020	D;D
Vest4		0.69
MPC		0.58
ClinPred		0.016	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113288277; hg19: chr1-979748;