rs199680125

chr1-1048186-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_198576.4(AGRN):c.3926G>A(p.Arg1309Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,569,432 control chromosomes in the GnomAD database, including 1 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1309W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.24

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007351905).
• BP6: Variant 1-1048186-G-A is Benign according to our data. Variant chr1-1048186-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00135 (205/152044) while in subpopulation AFR AF= 0.00478 (198/41462). AF 95% confidence interval is 0.00423. There are 1 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.3926G>A	p.Arg1309Gln	missense_variant	23/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.3926G>A	p.Arg1309Gln	missense_variant	23/36	1	NM_198576.4	P1
AGRN	ENST00000651234.1	c.3611G>A	p.Arg1204Gln	missense_variant	22/38
AGRN	ENST00000652369.1	c.3611G>A	p.Arg1204Gln	missense_variant	22/35
AGRN	ENST00000620552.4	c.3512G>A	p.Arg1171Gln	missense_variant	23/39	5

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 151932 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00479

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000374 AC: 65 AN: 174004 Hom.: 0 AF XY: 0.000316 AC XY: 30 AN XY: 94884

Gnomad AFR exome AF: 0.00551

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000720

Gnomad SAS exome AF: 0.0000810

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 178 AN: 1417388 Hom.: 0 Cov.: 35 AF XY: 0.000108 AC XY: 76 AN XY: 702078

Gnomad4 AFR exome AF: 0.00397

Gnomad4 AMR exome AF: 0.000219

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000805

Gnomad4 SAS exome AF: 0.0000368

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000165

Gnomad4 OTH exome AF: 0.000272

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152044 Hom.: 1 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74324

Gnomad4 AFR AF: 0.00478

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.00149

ESP6500AA AF: 0.00307 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000330 AC: 38

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2020

See Variant Classification Assertion Criteria. -

Congenital myasthenic syndrome 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	14
Dann	Benign	0.96
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0074	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.048
Sift	Benign	0.22	T;.
Sift4G	Benign	0.20	T;T
Vest4		0.14
MVP		0.73
MPC		0.14
ClinPred		0.0072	T
GERP RS		2.4
gMVP		0.31

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: rs199680125; hg19: chr1-983566;