chr1-1050763-G-T

Position:

• chr1-1050763-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_198576.4(AGRN):​c.5179G>T​(p.Val1727Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 3.93

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 1-1050763-G-T is Pathogenic according to our data. Variant chr1-1050763-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126555.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5179G>T	p.Val1727Phe	missense_variant	30/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5179G>T	p.Val1727Phe	missense_variant	30/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000651234.1	c.4864G>T	p.Val1622Phe	missense_variant	29/38			ENSP00000499046
AGRN	ENST00000652369.1	c.4864G>T	p.Val1622Phe	missense_variant	29/35			ENSP00000498543
AGRN	ENST00000620552.4	c.4765G>T	p.Val1589Phe	missense_variant	30/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451708 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 721960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 8 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 14, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects AGRN function (PMID: 22205389, 30994901). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 126555). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 22205389, 33756069). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1727 of the AGRN protein (p.Val1727Phe). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2012	- -

Congenital myasthenic syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D;.
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.91
MutPred		0.66		Loss of catalytic residue at V1727 (P = 0.0849);.;
MVP		0.92
MPC		0.66
ClinPred		0.97	D
GERP RS		4.4
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs587777298; hg19: chr1-986143;