chr1-1020183-G-C

Position:

• chr1-1020183-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198576.4(AGRN):​c.11G>C​(p.Arg4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,333,304 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., cov: 31)
  • Exomes 𝑓: 0.00099 (18 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018983781).
• BP6: Variant 1-1020183-G-C is Benign according to our data. Variant chr1-1020183-G-C is described in ClinVar as [Benign]. Clinvar id is 387476.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 = 0.012 (1806/150780) while in subpopulation AFR AF= 0.0419 (1731/41268). AF 95% confidence interval is 0.0403. There are 26 homozygotes in gnomad4. There are 859 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.11G>C	p.Arg4Pro	missense_variant	1/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.11G>C	p.Arg4Pro	missense_variant	1/36	1	NM_198576.4	P1
AGRN	ENST00000620552.4	c.-404G>C		5_prime_UTR_variant	1/39	5

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1806 AN: 150674 Hom.: 26 Cov.: 31

Gnomad AFR AF: 0.0421

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00317

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: 0.000133

Gnomad OTH AF: 0.00871

GnomAD3 exomes AF: 0.000944 AC: 25 AN: 26472 Hom.: 1 AF XY: 0.000552 AC XY: 9 AN XY: 16290

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000985

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.000994 AC: 1176 AN: 1182524 Hom.: 18 Cov.: 29 AF XY: 0.000842 AC XY: 487 AN XY: 578112

Gnomad4 AFR exome AF: 0.0427

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000393

Gnomad4 SAS exome AF: 0.0000418

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.0120 AC: 1806 AN: 150780 Hom.: 26 Cov.: 31 AF XY: 0.0117 AC XY: 859 AN XY: 73662

Gnomad4 AFR AF: 0.0419

Gnomad4 AMR AF: 0.00316

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.00862

Alfa AF: 0.00232 Hom.: 0

ExAC AF: 0.000423 AC: 6

Asia WGS AF: 0.00118 AC: 4 AN: 3410

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

AGRN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.21
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.13
Sift	Benign	0.26	T
Sift4G	Benign	0.30	T
Vest4		0.071
MVP		0.55
MPC		0.63
ClinPred		0.0047	T
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
gMVP		0.36

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: rs539283387; hg19: chr1-955563;