1-1050014-G-C

Variant names:

• chr1-1050014-G-C
• NM_198576.4:c.4856G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198576.4(AGRN):​c.4856G>C​(p.Arg1619Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,858 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R1619H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.21

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.4856G>C	p.Arg1619Pro	missense_variant	Exon 27 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.4856G>C	p.Arg1619Pro	missense_variant	Exon 27 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.4541G>C	p.Arg1514Pro	missense_variant	Exon 26 of 38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.4541G>C	p.Arg1514Pro	missense_variant	Exon 26 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.4442G>C	p.Arg1481Pro	missense_variant	Exon 27 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455858 Hom.: 0 Cov.: 71 AF XY: 0.00 AC XY: 0 AN XY: 723898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	18
DANN	Benign	0.97
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0020	D;D
Vest4		0.76
MutPred		0.61		Gain of glycosylation at R1619 (P = 0.0571);.;
MVP		0.83
MPC		0.63
ClinPred		0.97	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-985394;