rs587777645
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001080510.5(METTL23):c.282_286delAGATA(p.Gln94HisfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,578 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
METTL23
NM_001080510.5 frameshift
NM_001080510.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.58
Publications
2 publications found
Genes affected
METTL23 (HGNC:26988): (methyltransferase 23, arginine) The protein encoded by this gene functions as a transcription factor regulator in the transcriptional pathway for human cognition. It is a partner of the alpha subunit of the GA-binding protein transcription factor. Mutations in this gene cause mild autosomal recessive intellectual disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]
METTL23 Gene-Disease associations (from GenCC):
- intellectual disability, autosomal recessive 44Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- autosomal recessive non-syndromic intellectual disabilityInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-76733173-CAAGAT-C is Pathogenic according to our data. Variant chr17-76733173-CAAGAT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 144024.Status of the report is no_assertion_criteria_provided, 0 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001080510.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| METTL23 | NM_001080510.5 | MANE Select | c.282_286delAGATA | p.Gln94HisfsTer6 | frameshift | Exon 3 of 5 | NP_001073979.3 | ||
| METTL23 | NM_001206983.3 | c.282_286delAGATA | p.Gln94HisfsTer6 | frameshift | Exon 3 of 5 | NP_001193912.1 | |||
| METTL23 | NM_001206984.3 | c.282_286delAGATA | p.Gln94HisfsTer6 | frameshift | Exon 3 of 5 | NP_001193913.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| METTL23 | ENST00000341249.11 | TSL:1 MANE Select | c.282_286delAGATA | p.Gln94HisfsTer6 | frameshift | Exon 3 of 5 | ENSP00000341543.5 | ||
| METTL23 | ENST00000590964.5 | TSL:1 | c.81_85delAGATA | p.Gln27HisfsTer6 | frameshift | Exon 2 of 4 | ENSP00000465890.1 | ||
| ENSG00000267168 | ENST00000587459.1 | TSL:5 | c.198_202delAGATA | p.Gln66HisfsTer6 | frameshift | Exon 1 of 2 | ENSP00000466829.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461578Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727044 show subpopulations
GnomAD4 exome
AF:
AC:
2
AN:
1461578
Hom.:
AF XY:
AC XY:
1
AN XY:
727044
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33478
American (AMR)
AF:
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26126
East Asian (EAS)
AF:
AC:
0
AN:
39698
South Asian (SAS)
AF:
AC:
1
AN:
86218
European-Finnish (FIN)
AF:
AC:
0
AN:
53390
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111812
Other (OTH)
AF:
AC:
0
AN:
60372
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:no assertion criteria provided
Pathogenic
VUS
Benign
Condition
1
-
-
Intellectual disability, autosomal recessive 44 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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