1-1048069-C-A

Position:

• chr1-1048069-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198576.4(AGRN):​c.3809C>A​(p.Thr1270Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.949

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.3809C>A	p.Thr1270Lys	missense_variant	23/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.3809C>A	p.Thr1270Lys	missense_variant	23/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000651234.1	c.3494C>A	p.Thr1165Lys	missense_variant	22/38			ENSP00000499046
AGRN	ENST00000652369.1	c.3494C>A	p.Thr1165Lys	missense_variant	22/35			ENSP00000498543
AGRN	ENST00000620552.4	c.3395C>A	p.Thr1132Lys	missense_variant	23/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1431202 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 710784

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Benign	-0.0061
Eigen_PC	Benign	0.00053
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.62	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Benign	0.28
Sift	Uncertain	0.010	D;.
Sift4G	Uncertain	0.0040	D;D
Vest4		0.42
MutPred		0.44		Loss of phosphorylation at T1270 (P = 0.0172);.;
MVP		0.82
MPC		0.51
ClinPred		0.93	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.48

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: chr1-983449;