rs142286944

Positions:

• chr1-1050417-A-G

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.4977-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,612,724 control chromosomes in the GnomAD database, including 655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (51 hom., cov: 33)
  • Exomes 𝑓: 0.026 (604 hom.)
• Consequence: AGRN NM_198576.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002238
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.27

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=-0.88).
• BP6: Variant 1-1050417-A-G is Benign according to our data. Variant chr1-1050417-A-G is described in ClinVar as [Benign]. Clinvar id is 263193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1050417-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0185 (2807/152140) while in subpopulation NFE AF= 0.0304 (2068/67924). AF 95% confidence interval is 0.0294. There are 51 homozygotes in gnomad4. There are 1299 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 51 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.4977-10A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.4977-10A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000620552.4	c.4563-10A>G		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000484607
AGRN	ENST00000651234.1	c.4662-10A>G		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000499046
AGRN	ENST00000652369.1	c.4662-10A>G		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000498543

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2812 AN: 152022 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.00464

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.00923

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.0184 AC: 4542 AN: 247310 Hom.: 75 AF XY: 0.0191 AC XY: 2576 AN XY: 134618

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.00834

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.0194

Gnomad FIN exome AF: 0.00979

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0265 AC: 38659 AN: 1460584 Hom.: 604 Cov.: 34 AF XY: 0.0265 AC XY: 19230 AN XY: 726614

Gnomad4 AFR exome AF: 0.00373

Gnomad4 AMR exome AF: 0.00862

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0207

Gnomad4 FIN exome AF: 0.00934

Gnomad4 NFE exome AF: 0.0304

Gnomad4 OTH exome AF: 0.0247

GnomAD4 genome AF: 0.0185 AC: 2807 AN: 152140 Hom.: 51 Cov.: 33 AF XY: 0.0175 AC XY: 1299 AN XY: 74374

Gnomad4 AFR AF: 0.00462

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.0158

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0242

Gnomad4 FIN AF: 0.00923

Gnomad4 NFE AF: 0.0304

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0233 Hom.: 13

Bravo AF: 0.0173

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 06, 2020	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.86
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		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: rs142286944; hg19: chr1-985797;