rs144245019

chr1-1051352-G-Achr1-1051352-G-Cchr1-1051352-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198576.4(AGRN):c.5353G>A(p.Asp1785Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00951 in 1,566,410 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1785H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0068 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0098 (86 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.0220

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0104987025).
• BP6: Variant 1-1051352-G-A is Benign according to our data. Variant chr1-1051352-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128314.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr1-1051352-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00677 (1030/152056) while in subpopulation NFE AF= 0.0115 (778/67918). AF 95% confidence interval is 0.0108. There are 1 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.5353G>A	p.Asp1785Asn	missense_variant	31/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.5353G>A	p.Asp1785Asn	missense_variant	31/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.5050G>A	p.Asp1684Asn	missense_variant	31/38
AGRN	ENST00000652369.1	c.5038G>A	p.Asp1680Asn	missense_variant	30/35
AGRN	ENST00000620552.4	c.4951G>A	p.Asp1651Asn	missense_variant	32/39	5

Frequencies

GnomAD3 genomes AF: 0.00679 AC: 1031 AN: 151938 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00237

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00633 AC: 1089 AN: 172002 Hom.: 3 AF XY: 0.00614 AC XY: 567 AN XY: 92368

Gnomad AFR exome AF: 0.00164

Gnomad AMR exome AF: 0.00443

Gnomad ASJ exome AF: 0.00764

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000953

Gnomad FIN exome AF: 0.00315

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00624

GnomAD4 exome AF: 0.00980 AC: 13859 AN: 1414354 Hom.: 86 Cov.: 37 AF XY: 0.00972 AC XY: 6798 AN XY: 699158

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00476

Gnomad4 ASJ exome AF: 0.00708

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.00271

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.00766

GnomAD4 genome AF: 0.00677 AC: 1030 AN: 152056 Hom.: 1 Cov.: 33 AF XY: 0.00601 AC XY: 447 AN XY: 74350

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00237

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00959 Hom.: 4

Bravo AF: 0.00710

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00230 AC: 10

ESP6500EA AF: 0.0116 AC: 99

ExAC AF: 0.00511 AC: 595

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2013	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	AGRN: BP4, BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 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. -

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	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.5
Dann	Benign	0.95
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.18	T;T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.12	N;.
REVEL	Benign	0.069
Sift	Benign	0.56	T;.
Sift4G	Benign	0.48	T;T
Vest4		0.18
MVP		0.48
MPC		0.12
ClinPred		0.0023	T
GERP RS		-2.1
gMVP		0.38

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: rs144245019; hg19: chr1-986732; COSMIC: COSV99062175; COSMIC: COSV99062175;