chr1-1050785-G-A

Variant names:

• chr1-1050785-G-A
• rs145444272
• NM_198576.4:c.5201G>A

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.5201G>A​(p.Arg1734His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,601,112 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1734C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (17 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.51
• Publications: 9 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=0.01095891).
• BP6: Variant 1-1050785-G-A is Benign according to our data. Variant chr1-1050785-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263195.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 = 0.00376 (572/152242) while in subpopulation NFE AF = 0.00435 (296/67980). AF 95% confidence interval is 0.00395. There are 3 homozygotes in GnomAd4. There are 328 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.5201G>A	p.Arg1734His	missense	Exon 30 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5201G>A	p.Arg1734His	missense	Exon 30 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.4886G>A	p.Arg1629His	missense	Exon 29 of 36	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.5201G>A	p.Arg1734His	missense	Exon 30 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.4886G>A	p.Arg1629His	missense	Exon 29 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.4886G>A	p.Arg1629His	missense	Exon 29 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152124 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00345 AC: 788 AN: 228248 AF XY: 0.00347

Gnomad AFR exome AF: 0.000759

Gnomad AMR exome AF: 0.000816

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.00390

Gnomad OTH exome AF: 0.00320

GnomAD4 exome AF: 0.00386 AC: 5593 AN: 1448870 Hom.: 17 Cov.: 34 AF XY: 0.00377 AC XY: 2718 AN XY: 720514

African (AFR) AF: 0.000360 AC: 12 AN: 33354

American (AMR) AF: 0.000822 AC: 36 AN: 43788

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 45 AN: 25898

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39376

South Asian (SAS) AF: 0.000270 AC: 23 AN: 85028

European-Finnish (FIN) AF: 0.0174 AC: 837 AN: 47980

Middle Eastern (MID) AF: 0.00140 AC: 6 AN: 4292

European-Non Finnish (NFE) AF: 0.00402 AC: 4454 AN: 1109292

Other (OTH) AF: 0.00299 AC: 179 AN: 59862

GnomAD4 genome AF: 0.00376 AC: 572 AN: 152242 Hom.: 3 Cov.: 33 AF XY: 0.00441 AC XY: 328 AN XY: 74424

African (AFR) AF: 0.000794 AC: 33 AN: 41550

American (AMR) AF: 0.000784 AC: 12 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.0205 AC: 218 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00435 AC: 296 AN: 67980

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00230 Hom.: 7

Bravo AF: 0.00238

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00408 AC: 35

ExAC AF: 0.00292 AC: 352

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Sep 27, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Dec 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19631309)

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AGRN: PP3, BS2

Congenital myasthenic syndrome 8 Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Vest4		0.65
MVP		0.87
MPC		0.64
ClinPred		0.012	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.78
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs145444272; hg19: chr1-986165; COSMIC: COSV106113334; COSMIC: COSV106113334;