1-1044368-A-T

Variant names:

• chr1-1044368-A-T
• rs113288277
• NM_198576.4:c.2183A>T

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: 5.45
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 128294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 105 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.2183A>T	p.Glu728Val	missense_variant	Exon 12 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.2183A>T	p.Glu728Val	missense_variant	Exon 12 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.1868A>T	p.Glu623Val	missense_variant	Exon 11 of 38			ENSP00000499046.1
AGRN	ENST00000652369.2	c.1868A>T	p.Glu623Val	missense_variant	Exon 11 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.1769A>T	p.Glu590Val	missense_variant	Exon 12 of 39	5		ENSP00000484607.1

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

GnomAD2 exomes AF: 0.0298 AC: 7415 AN: 249164 AF XY: 0.0308

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 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

African (AFR) AF: 0.00511 AC: 171 AN: 33470

American (AMR) AF: 0.0160 AC: 717 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0437 AC: 1141 AN: 26120

East Asian (EAS) AF: 0.00292 AC: 116 AN: 39690

South Asian (SAS) AF: 0.0235 AC: 2030 AN: 86258

European-Finnish (FIN) AF: 0.0348 AC: 1820 AN: 52298

Middle Eastern (MID) AF: 0.0296 AC: 171 AN: 5768

European-Non Finnish (NFE) AF: 0.0425 AC: 47294 AN: 1111830

Other (OTH) AF: 0.0359 AC: 2165 AN: 60362

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

African (AFR) AF: 0.00671 AC: 278 AN: 41418

American (AMR) AF: 0.0213 AC: 326 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3470

East Asian (EAS) AF: 0.00504 AC: 26 AN: 5158

South Asian (SAS) AF: 0.0281 AC: 135 AN: 4804

European-Finnish (FIN) AF: 0.0388 AC: 411 AN: 10580

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0448 AC: 3044 AN: 67948

Other (OTH) AF: 0.0253 AC: 53 AN: 2098

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 26, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 06, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital myasthenic syndrome 8 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
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;.
PhyloP100		5.5
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
Mutation Taster		=86/14	polymorphism (auto)

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

Other links and lift over

dbSNP: rs113288277; hg19: chr1-979748;