1-1050014-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_198576.4(AGRN):​c.4856G>T​(p.Arg1619Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,607,884 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. R1619H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

2
6
9

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.21
Variant links:
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]

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ACMG classification

Classification made for transcript

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, 0.809

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AGRNNM_198576.4 linkc.4856G>T p.Arg1619Leu missense_variant Exon 27 of 36 ENST00000379370.7 NP_940978.2 O00468-6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AGRNENST00000379370.7 linkc.4856G>T p.Arg1619Leu missense_variant Exon 27 of 36 1 NM_198576.4 ENSP00000368678.2 O00468-6
AGRNENST00000651234.1 linkc.4541G>T p.Arg1514Leu missense_variant Exon 26 of 38 ENSP00000499046.1 A0A494C1I6
AGRNENST00000652369.1 linkc.4541G>T p.Arg1514Leu missense_variant Exon 26 of 35 ENSP00000498543.1 A0A494C0G5
AGRNENST00000620552.4 linkc.4442G>T p.Arg1481Leu missense_variant Exon 27 of 39 5 ENSP00000484607.1 A0A087X208

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152026
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000440
AC:
1
AN:
227440
Hom.:
0
AF XY:
0.00000796
AC XY:
1
AN XY:
125694
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000101
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000412
AC:
6
AN:
1455858
Hom.:
0
Cov.:
71
AF XY:
0.00000414
AC XY:
3
AN XY:
723898
show subpopulations
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:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152026
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74264
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.00000843
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.0059
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
17
DANN
Uncertain
0.99
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.53
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
1.0
L;.
PrimateAI
Benign
0.45
T
PROVEAN
Pathogenic
-4.8
D;.
REVEL
Uncertain
0.34
Sift
Benign
0.047
D;.
Sift4G
Uncertain
0.0020
D;D
Vest4
0.70
MutPred
0.54
Loss of phosphorylation at T1622 (P = 0.0503);.;
MVP
0.76
MPC
0.43
ClinPred
0.95
D
GERP RS
1.9
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs753675816; hg19: chr1-985394; API