chr1-1048116-C-T

Variant names:

• chr1-1048116-C-T
• rs760218476
• NM_198576.4:c.3856C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198576.4(AGRN):​c.3856C>T​(p.Pro1286Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000424 in 1,416,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1286T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.391

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05339098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.3856C>T	p.Pro1286Ser	missense_variant	Exon 23 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.3856C>T	p.Pro1286Ser	missense_variant	Exon 23 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.3541C>T	p.Pro1181Ser	missense_variant	Exon 22 of 38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.3541C>T	p.Pro1181Ser	missense_variant	Exon 22 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.3442C>T	p.Pro1148Ser	missense_variant	Exon 23 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000222 AC: 4 AN: 179912 Hom.: 0 AF XY: 0.0000203 AC XY: 2 AN XY: 98352

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000424 AC: 6 AN: 1416738 Hom.: 0 Cov.: 36 AF XY: 0.00000285 AC XY: 2 AN XY: 702428

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000973

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000254 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3856C>T (p.P1286S) alteration is located in exon 23 (coding exon 23) of the AGRN gene. This alteration results from a C to T substitution at nucleotide position 3856, causing the proline (P) at amino acid position 1286 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Uncertain	1.0
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.66	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.76	N;.
REVEL	Benign	0.067
Sift	Benign	0.47	T;.
Sift4G	Uncertain	0.052	T;T
Vest4		0.10
MutPred		0.21		Gain of phosphorylation at P1286 (P = 0.012);.;
MVP		0.75
MPC		0.14
ClinPred		0.047	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760218476; hg19: chr1-983496;