chr1-155339342-C-A
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_018489.3(ASH1L):c.8487G>T(p.Lys2829Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
ASH1L
NM_018489.3 missense
NM_018489.3 missense
Scores
5
9
5
Clinical Significance
Conservation
PhyloP100: 4.67
Genes affected
ASH1L (HGNC:19088): (ASH1 like histone lysine methyltransferase) This gene encodes a member of the trithorax group of transcriptional activators. The protein contains four AT hooks, a SET domain, a PHD-finger motif, and a bromodomain. It is localized to many small speckles in the nucleus, and also to cell-cell tight junctions. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP2
Missense variant where missense usually causes diseases, ASH1L
BS2
High AC in GnomAdExome4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASH1L | NM_018489.3 | c.8487G>T | p.Lys2829Asn | missense_variant | 26/28 | ENST00000392403.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASH1L | ENST00000392403.8 | c.8487G>T | p.Lys2829Asn | missense_variant | 26/28 | 5 | NM_018489.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251424Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135888
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461440Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727018
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74324
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Intellectual disability, mild;C0036572:Seizure;C0454644:Delayed speech and language development Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | New York Genome Center | Dec 03, 2019 | The c.8487G>T (p.Lys2829Asn) variant substitutes a completely conserved Lysine for Asparagine at amino acid 2829/2965 (coding exon 26/28).This variant is found with low frequency in gnomAD (5 heterozygotes, 0 homozygotes; allele frequency: 1.99e-5) and ExAC (2 heterozygotes, 0 homozygotes; allele frequency: 1.65e-5), suggesting it is not a common benign variant in the populations represented in these databases. In silico algorithms do not agree on the effect of this variant, as it is predicted Neutral (Provean; score: -2.13) and Damaging (SIFT; score: 0.001) to the function of the canonical transcript. To our current knowledge has not been reported in affected individuals in the literature. The p.Lys2829 residue does not map to a specific domain and is C-terminal to the highly conserved BAH domain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Loss of methylation at K2834 (P = 0.0086);.;
MVP
MPC
1.5
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at