rs751987634

Positions:

• chr1-1046604-C-G
• chr1-1046604-C-T

Variant summary

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

The NM_198576.4(AGRN):​c.3119C>G​(p.Thr1040Arg) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1040M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.87

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.3119C>G	p.Thr1040Arg	missense_variant	18/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.3119C>G	p.Thr1040Arg	missense_variant	18/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.2804C>G	p.Thr935Arg	missense_variant	17/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.2804C>G	p.Thr935Arg	missense_variant	17/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.2705C>G	p.Thr902Arg	missense_variant	18/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	0.026
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0090	D;.
Sift4G	Benign	0.16	T;T
Vest4		0.66
MutPred		0.20		Loss of glycosylation at T1040 (P = 0.008);.;
MVP		0.83
MPC		0.41
ClinPred		0.67	D
GERP RS		3.4
gMVP		0.55

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: chr1-981984;