rs199476396

Positions:

• chr1-1050575-G-A
• chr1-1050575-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000379370.7(AGRN):​c.5125G>A​(p.Gly1709Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AGRN ENST00000379370.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.28

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5125G>A	p.Gly1709Arg	missense_variant	29/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5125G>A	p.Gly1709Arg	missense_variant	29/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000651234.1	c.4810G>A	p.Gly1604Arg	missense_variant	28/38			ENSP00000499046
AGRN	ENST00000652369.1	c.4810G>A	p.Gly1604Arg	missense_variant	28/35			ENSP00000498543
AGRN	ENST00000620552.4	c.4711G>A	p.Gly1571Arg	missense_variant	29/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458278 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 725178

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0020	D;D
Vest4		0.83
MutPred		0.81		Gain of MoRF binding (P = 0.0205);.;
MVP		0.89
MPC		0.63
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.92

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: rs199476396; hg19: chr1-985955;