rs112073270

Variant names:

• chr1-1051351-C-T
• rs112073270
• NM_198576.4:c.5352C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198576.4(AGRN):​c.5352C>T​(p.Phe1784Phe) 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 NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.05
• Publications: 0 publications found

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]

AGRN Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 8

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.5352C>T	p.Phe1784Phe	synonymous	Exon 31 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5364C>T	p.Phe1788Phe	synonymous	Exon 32 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.5049C>T	p.Phe1683Phe	synonymous	Exon 31 of 36	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.5352C>T	p.Phe1784Phe	synonymous	Exon 31 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.5049C>T	p.Phe1683Phe	synonymous	Exon 31 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.5037C>T	p.Phe1679Phe	synonymous	Exon 30 of 35	ENSP00000498543.1	A0A494C0G5

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

GnomAD2 exomes AF: 0.00106 AC: 183 AN: 172386 AF XY: 0.000735

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 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

African (AFR) AF: 0.0152 AC: 500 AN: 32808

American (AMR) AF: 0.000798 AC: 30 AN: 37586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25272

East Asian (EAS) AF: 0.00 AC: 0 AN: 37760

South Asian (SAS) AF: 0.0000993 AC: 8 AN: 80554

European-Finnish (FIN) AF: 0.0000210 AC: 1 AN: 47662

Middle Eastern (MID) AF: 0.000186 AC: 1 AN: 5388

European-Non Finnish (NFE) AF: 0.000105 AC: 114 AN: 1088854

Other (OTH) AF: 0.000972 AC: 57 AN: 58654

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

African (AFR) AF: 0.0169 AC: 700 AN: 41508

American (AMR) AF: 0.00137 AC: 21 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000949 AC: 1 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67964

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00220 Hom.: 2

Bravo AF: 0.00529

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital myasthenic syndrome 8 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.72
DANN	Benign	0.72
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs112073270; hg19: chr1-986731;