chr1-1053827-G-C

Position:

• chr1-1053827-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198576.4(AGRN):​c.5726G>C​(p.Ser1909Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00364 in 1,611,076 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict 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. S1909R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0072 (36 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (157 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.71

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057588816).
• BP6: Variant 1-1053827-G-C is Benign according to our data. Variant chr1-1053827-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 128318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5726G>C	p.Ser1909Thr	missense_variant	34/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5726G>C	p.Ser1909Thr	missense_variant	34/36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes AF: 0.00711 AC: 1082 AN: 152280 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00961

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.0125 AC: 3043 AN: 243286 Hom.: 106 AF XY: 0.00929 AC XY: 1228 AN XY: 132242

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.0821

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00702

Gnomad SAS exome AF: 0.000302

Gnomad FIN exome AF: 0.0000489

Gnomad NFE exome AF: 0.000464

Gnomad OTH exome AF: 0.00894

GnomAD4 exome AF: 0.00327 AC: 4764 AN: 1458678 Hom.: 157 Cov.: 35 AF XY: 0.00283 AC XY: 2054 AN XY: 725460

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.0784

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0204

Gnomad4 SAS exome AF: 0.000198

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000220

Gnomad4 OTH exome AF: 0.00307

GnomAD4 genome AF: 0.00717 AC: 1093 AN: 152398 Hom.: 36 Cov.: 33 AF XY: 0.00782 AC XY: 583 AN XY: 74516

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.0596

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00982

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00248 Hom.: 1

Bravo AF: 0.0112

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00910 AC: 1102

Asia WGS AF: 0.00520 AC: 18 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

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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2018	- -

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_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.50
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.32
Sift	Benign	0.58	T;.
Sift4G	Uncertain	0.036	D;D
Vest4		0.53
MPC		0.39
ClinPred		0.035	T
GERP RS		-0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.55

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: rs74685771; hg19: chr1-989207; COSMIC: COSV101038613; COSMIC: COSV101038613;