rs764659938

chr1-1020216-C-Gchr1-1020216-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_198576.4(AGRN):c.44C>G(p.Pro15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,396,028 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P15L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.41

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04079905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.44C>G	p.Pro15Arg	missense_variant	1/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.44C>G	p.Pro15Arg	missense_variant	1/36	1	NM_198576.4	P1
AGRN	ENST00000620552.4	c.-371C>G		5_prime_UTR_variant	1/39	5

Frequencies

GnomAD3 genomes AF: 0.000740 AC: 112 AN: 151444 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000609 AC: 31 AN: 50884 Hom.: 0 AF XY: 0.000688 AC XY: 21 AN XY: 30530

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000860

Gnomad FIN exome AF: 0.000480

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00107 AC: 1334 AN: 1244584 Hom.: 1 Cov.: 29 AF XY: 0.00104 AC XY: 636 AN XY: 611732

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000583

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000374

Gnomad4 SAS exome AF: 0.0000166

Gnomad4 FIN exome AF: 0.000346

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.000454

GnomAD4 genome AF: 0.000740 AC: 112 AN: 151444 Hom.: 1 Cov.: 31 AF XY: 0.000771 AC XY: 57 AN XY: 73958

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000193

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.00106 Hom.: 1

Bravo AF: 0.000676

ExAC AF: 0.000210 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 19, 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	19
Dann	Benign	0.18
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.18	N
REVEL	Benign	0.073
Sift	Benign	0.10	T
Sift4G	Benign	0.10	T
Vest4		0.17
MVP		0.67
MPC		0.46
ClinPred		0.075	T
GERP RS		0.71
gMVP		0.25

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: rs764659938; hg19: chr1-955596;