rs115191992

chr1-1043476-G-A

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.1603+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,599,186 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (29 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.891

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 (BayesDel_noAF=-0.85).
• BP6: Variant 1-1043476-G-A is Benign according to our data. Variant chr1-1043476-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263164.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 = 0.00679 (1033/152234) while in subpopulation AFR AF= 0.0108 (450/41542). AF 95% confidence interval is 0.01. There are 8 homozygotes in gnomad4. There are 489 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.1603+19G>A		intron_variant		ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.1603+19G>A		intron_variant		1	NM_198576.4	P1
AGRN	ENST00000620552.4	c.1189+19G>A		intron_variant		5
AGRN	ENST00000651234.1	c.1288+19G>A		intron_variant
AGRN	ENST00000652369.1	c.1288+19G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00677 AC: 1030 AN: 152118 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00687

Gnomad OTH AF: 0.00767

GnomAD3 exomes AF: 0.00492 AC: 1080 AN: 219586 Hom.: 1 AF XY: 0.00479 AC XY: 579 AN XY: 120938

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.00300

Gnomad ASJ exome AF: 0.000525

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00204

Gnomad FIN exome AF: 0.000994

Gnomad NFE exome AF: 0.00734

Gnomad OTH exome AF: 0.00501

GnomAD4 exome AF: 0.00591 AC: 8546 AN: 1446952 Hom.: 29 Cov.: 35 AF XY: 0.00580 AC XY: 4178 AN XY: 720010

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.00316

Gnomad4 ASJ exome AF: 0.000809

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00299

Gnomad4 FIN exome AF: 0.00141

Gnomad4 NFE exome AF: 0.00664

Gnomad4 OTH exome AF: 0.00511

GnomAD4 genome AF: 0.00679 AC: 1033 AN: 152234 Hom.: 8 Cov.: 33 AF XY: 0.00657 AC XY: 489 AN XY: 74414

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00434

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00687

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.00607 Hom.: 1

Bravo AF: 0.00746

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2017	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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 26, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	12
Dann	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs115191992; hg19: chr1-978856; COSMIC: COSV65070034; COSMIC: COSV65070034;