NM_198576.4:c.5623G>T

Variant names:

• chr1-1051787-G-T
• NM_198576.4:c.5623G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198576.4(AGRN):​c.5623G>T​(p.Val1875Phe) 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. 11/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.165

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23947483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.5623G>T	p.Val1875Phe	missense_variant	Exon 33 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.5623G>T	p.Val1875Phe	missense_variant	Exon 33 of 36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 85

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.56
DANN	Uncertain	0.99
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.95
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.90	T
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.019	D;.
Sift4G	Uncertain	0.0080	D;D
Vest4		0.42
MVP		0.50
MPC		0.21
ClinPred		0.18	T
GERP RS		-2.2
gMVP		0.64

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: chr1-987167; COSMIC: COSV65070533; COSMIC: COSV65070533;