1-1051504-G-T

Variant names:

• chr1-1051504-G-T
• rs1356478300
• NM_198576.4:c.5422G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198576.4(AGRN):​c.5422G>T​(p.Val1808Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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. V1808M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96
• Publications: 0 publications found

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]

AGRN Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15642554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5422G>T	p.Val1808Leu	missense_variant	Exon 32 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5422G>T	p.Val1808Leu	missense_variant	Exon 32 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.5119G>T	p.Val1707Leu	missense_variant	Exon 32 of 38			ENSP00000499046.1
AGRN	ENST00000652369.2	c.5107G>T	p.Val1703Leu	missense_variant	Exon 31 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.5020G>T	p.Val1674Leu	missense_variant	Exon 33 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1416546 Hom.: 0 Cov.: 85 AF XY: 0.00 AC XY: 0 AN XY: 701002

African (AFR) AF: 0.00 AC: 0 AN: 32898

American (AMR) AF: 0.00 AC: 0 AN: 40856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25264

East Asian (EAS) AF: 0.00 AC: 0 AN: 38290

South Asian (SAS) AF: 0.00 AC: 0 AN: 82086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092140

Other (OTH) AF: 0.00 AC: 0 AN: 58682

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.83
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.81	T
PhyloP100		2.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.14
Sift	Benign	0.56	T;.
Sift4G	Uncertain	0.053	T;T
Vest4		0.37
MutPred		0.38		Gain of loop (P = 0.1069);.;
MVP		0.66
MPC		0.14
ClinPred		0.089	T
GERP RS		4.1
gMVP		0.33
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1356478300; hg19: chr1-986884;