1-35893699-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_012199.5(AGO1):​c.538T>C​(p.Phe180Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

AGO1
NM_012199.5 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.82
Variant links:
Genes affected
AGO1 (HGNC:3262): (argonaute RISC component 1) This gene encodes a member of the argonaute family of proteins, which associate with small RNAs and have important roles in RNA interference (RNAi) and RNA silencing. This protein binds to microRNAs (miRNAs) or small interfering RNAs (siRNAs) and represses translation of mRNAs that are complementary to them. It is also involved in transcriptional gene silencing (TGS) of promoter regions that are complementary to bound short antigene RNAs (agRNAs), as well as in the degradation of miRNA-bound mRNA targets. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. A recent study showed this gene to be an authentic stop codon readthrough target, and that its mRNA could give rise to an additional C-terminally extended isoform by use of an alternative in-frame translation termination codon. [provided by RefSeq, Nov 2015]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGO1NM_012199.5 linkc.538T>C p.Phe180Leu missense_variant 5/19 ENST00000373204.6 NP_036331.1 Q9UL18B2RAD8
AGO1NM_001317122.2 linkc.538T>C p.Phe180Leu missense_variant 5/19 NP_001304051.1 Q9UL18A0A6I8PTZ8B2RAD8
AGO1NM_001317123.2 linkc.313T>C p.Phe105Leu missense_variant 5/19 NP_001304052.1 Q9UL18Q5TA58B2RAD8B3KME0
AGO1XM_011541236.3 linkc.538T>C p.Phe180Leu missense_variant 5/19 XP_011539538.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGO1ENST00000373204.6 linkc.538T>C p.Phe180Leu missense_variant 5/191 NM_012199.5 ENSP00000362300.4 Q9UL18

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, Cologne UniversityJun 07, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.62
.;D
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.023
T
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Benign
-0.72
T
MutationAssessor
Pathogenic
3.9
.;H
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.1
D;D
REVEL
Uncertain
0.57
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.034
D;D
Polyphen
1.0
.;D
Vest4
0.77
MutPred
0.78
.;Gain of disorder (P = 0.1799);
MVP
0.80
MPC
3.0
ClinPred
1.0
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.91
gMVP
0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-36359300; API