rs111818381

chr1-1049591-G-Achr1-1049591-G-C

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.4540G>A(p.Ala1514Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00947 in 1,590,108 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1514A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (83 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.43

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=0.0125926435).
• BP6: Variant 1-1049591-G-A is Benign according to our data. Variant chr1-1049591-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1049591-G-A is described in Lovd as [Likely_benign]. Variant chr1-1049591-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00762 (1160/152260) while in subpopulation NFE AF= 0.0114 (774/68008). AF 95% confidence interval is 0.0107. There are 9 homozygotes in gnomad4. There are 518 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.4540G>A	p.Ala1514Thr	missense_variant	26/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.4540G>A	p.Ala1514Thr	missense_variant	26/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.4225G>A	p.Ala1409Thr	missense_variant	25/38
AGRN	ENST00000652369.1	c.4225G>A	p.Ala1409Thr	missense_variant	25/35
AGRN	ENST00000620552.4	c.4126G>A	p.Ala1376Thr	missense_variant	26/39	5

Frequencies

GnomAD3 genomes AF: 0.00764 AC: 1162 AN: 152142 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00782 AC: 1602 AN: 204756 Hom.: 12 AF XY: 0.00788 AC XY: 874 AN XY: 110904

Gnomad AFR exome AF: 0.00201

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.0248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00298

Gnomad FIN exome AF: 0.00506

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00966 AC: 13896 AN: 1437848 Hom.: 83 Cov.: 44 AF XY: 0.00953 AC XY: 6794 AN XY: 713080

Gnomad4 AFR exome AF: 0.00172

Gnomad4 AMR exome AF: 0.00518

Gnomad4 ASJ exome AF: 0.0245

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00316

Gnomad4 FIN exome AF: 0.00495

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.00992

GnomAD4 genome AF: 0.00762 AC: 1160 AN: 152260 Hom.: 9 Cov.: 32 AF XY: 0.00696 AC XY: 518 AN XY: 74448

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0113 Hom.: 16

Bravo AF: 0.00801

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00184 AC: 8

ESP6500EA AF: 0.0110 AC: 94

ExAC AF: 0.00660 AC: 790

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2018	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. -
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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	AGRN: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 05, 2017	- -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.022
Dann	Benign	0.64
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.24	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.10	N;.
REVEL	Benign	0.12
Sift	Benign	0.59	T;.
Sift4G	Benign	0.49	T;T
Vest4		0.029
MVP		0.53
MPC		0.12
ClinPred		0.00028	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
gMVP		0.29

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: rs111818381; hg19: chr1-984971;