1-1020344-G-T

Variant names:

• chr1-1020344-G-T
• NM_198576.4:c.172G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198576.4(AGRN):​c.172G>T​(p.Asp58Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000745 in 1,342,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D58N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.172G>T	p.Asp58Tyr	missense_variant	Exon 1 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.172G>T	p.Asp58Tyr	missense_variant	Exon 1 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000620552	c.-243G>T		5_prime_UTR_variant	Exon 1 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.45e-7 AC: 1 AN: 1342724 Hom.: 0 Cov.: 32 AF XY: 0.00000151 AC XY: 1 AN XY: 662314

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: 0.0000220

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Uncertain	0.98
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	L
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.59
MutPred		0.74		Gain of MoRF binding (P = 0.0803);
MVP		0.62
MPC		0.53
ClinPred		0.94	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr1-955724;