rs112073270

Positions:

• chr1-1051351-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000379370.7(AGRN):​c.5352C>T​(p.Phe1784=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000927 in 1,566,626 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (4 hom.)
• Consequence: AGRN ENST00000379370.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.05

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-1051351-C-T is Benign according to our data. Variant chr1-1051351-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00488 (742/152088) while in subpopulation AFR AF= 0.0169 (700/41508). AF 95% confidence interval is 0.0158. There are 7 homozygotes in gnomad4. There are 335 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5352C>T	p.Phe1784=	synonymous_variant	31/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5352C>T	p.Phe1784=	synonymous_variant	31/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000651234.1	c.5049C>T	p.Phe1683=	synonymous_variant	31/38			ENSP00000499046
AGRN	ENST00000652369.1	c.5037C>T	p.Phe1679=	synonymous_variant	30/35			ENSP00000498543
AGRN	ENST00000620552.4	c.4950C>T	p.Phe1650=	synonymous_variant	32/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes AF: 0.00487 AC: 740 AN: 151970 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00106 AC: 183 AN: 172386 Hom.: 1 AF XY: 0.000735 AC XY: 68 AN XY: 92536

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.000720

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000414

Gnomad FIN exome AF: 0.0000664

Gnomad NFE exome AF: 0.0000717

Gnomad OTH exome AF: 0.000859

GnomAD4 exome AF: 0.000503 AC: 711 AN: 1414538 Hom.: 4 Cov.: 37 AF XY: 0.000461 AC XY: 322 AN XY: 699240

Gnomad4 AFR exome AF: 0.0152

Gnomad4 AMR exome AF: 0.000798

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000993

Gnomad4 FIN exome AF: 0.0000210

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.000972

GnomAD4 genome AF: 0.00488 AC: 742 AN: 152088 Hom.: 7 Cov.: 33 AF XY: 0.00451 AC XY: 335 AN XY: 74356

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000949

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00220 Hom.: 2

Bravo AF: 0.00529

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.72
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs112073270; hg19: chr1-986731;