rs148475305

chr1-1046472-C-A

Variant summary

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

The NM_198576.4(AGRN):c.2987C>A(p.Ala996Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,611,870 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.437

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=0.012793899).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.2987C>A	p.Ala996Glu	missense_variant	18/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.2987C>A	p.Ala996Glu	missense_variant	18/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.2672C>A	p.Ala891Glu	missense_variant	17/38
AGRN	ENST00000652369.1	c.2672C>A	p.Ala891Glu	missense_variant	17/35
AGRN	ENST00000620552.4	c.2573C>A	p.Ala858Glu	missense_variant	18/39	5

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00106

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000467 AC: 114 AN: 244164 Hom.: 0 AF XY: 0.000509 AC XY: 68 AN XY: 133524

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000932

Gnomad OTH exome AF: 0.000675

GnomAD4 exome AF: 0.00110 AC: 1606 AN: 1459646 Hom.: 2 Cov.: 38 AF XY: 0.00107 AC XY: 778 AN XY: 726098

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000962

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74426

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000884 Hom.: 0

Bravo AF: 0.000548

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000935 AC: 8

ExAC AF: 0.000579 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000712

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 28, 2022

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 996 of the AGRN protein (p.Ala996Glu). This variant is present in population databases (rs148475305, gnomAD 0.09%), 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: 474111). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	-0.31	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	6.2
Dann	Benign	0.59
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.66	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	N;.
REVEL	Uncertain	0.32
Sift	Benign	0.92	T;.
Sift4G	Benign	0.27	T;T
Vest4		0.35
MVP		0.72
MPC		0.38
ClinPred		0.0098	T
GERP RS		1.3
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148475305; hg19: chr1-981852;