1-1049998-G-A

Position:

• chr1-1049998-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_198576.4(AGRN):​c.4840G>A​(p.Glu1614Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,611,426 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (6 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.64

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.067908466).
• BP6: Variant 1-1049998-G-A is Benign according to our data. Variant chr1-1049998-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474139.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.4840G>A	p.Glu1614Lys	missense_variant	27/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.4840G>A	p.Glu1614Lys	missense_variant	27/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.4525G>A	p.Glu1509Lys	missense_variant	26/38
AGRN	ENST00000652369.1	c.4525G>A	p.Glu1509Lys	missense_variant	26/35
AGRN	ENST00000620552.4	c.4426G>A	p.Glu1476Lys	missense_variant	27/39	5

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152072 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000915 AC: 217 AN: 237190 Hom.: 1 AF XY: 0.000872 AC XY: 114 AN XY: 130764

Gnomad AFR exome AF: 0.000278

Gnomad AMR exome AF: 0.000853

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000661

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.00220 AC: 3207 AN: 1459240 Hom.: 6 Cov.: 72 AF XY: 0.00214 AC XY: 1551 AN XY: 725926

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00273

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.000887 AC XY: 66 AN XY: 74414

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00188

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00228 Hom.: 1

Bravo AF: 0.00116

ESP6500AA AF: 0.000457 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000696 AC: 83

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	AGRN: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 28, 2023	- -

Congenital myasthenic syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1614 of the AGRN protein (p.Glu1614Lys). This variant is present in population databases (rs147259096, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with AGRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 474139). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.96
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.44	N;.
MutationTaster	Benign	0.95	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.26
Sift	Benign	0.52	T;.
Sift4G	Uncertain	0.060	T;T
Vest4		0.58
MVP		0.71
MPC		0.17
ClinPred		0.0072	T
GERP RS		1.9
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147259096; hg19: chr1-985378;