rs541943893
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2
The NM_014159.7(SETD2):c.19C>T(p.Gln7Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,313,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
SETD2
NM_014159.7 stop_gained
NM_014159.7 stop_gained
Scores
3
2
2
Clinical Significance
Conservation
PhyloP100: 1.30
Genes affected
SETD2 (HGNC:18420): (SET domain containing 2, histone lysine methyltransferase) Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein belonging to a class of huntingtin interacting proteins characterized by WW motifs. This protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II. [provided by RefSeq, Aug 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 41 pathogenic variants in the truncated region.
BP6
?
Variant 3-47163906-G-A is Benign according to our data. Variant chr3-47163906-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521678.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000243 (37/151988) while in subpopulation AMR AF= 0.00229 (35/15264). AF 95% confidence interval is 0.00169. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 37 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SETD2 | NM_014159.7 | c.19C>T | p.Gln7Ter | stop_gained | 1/21 | ENST00000409792.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SETD2 | ENST00000409792.4 | c.19C>T | p.Gln7Ter | stop_gained | 1/21 | 5 | NM_014159.7 | P3 | |
SETD2 | ENST00000691544.1 | c.19C>T | p.Gln7Ter | stop_gained | 1/14 | ||||
SETD2 | ENST00000638947.2 | upstream_gene_variant | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000244 AC: 37AN: 151880Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000319 AC: 3AN: 94066Hom.: 0 AF XY: 0.0000192 AC XY: 1AN XY: 52216
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GnomAD4 exome AF: 0.0000396 AC: 46AN: 1161806Hom.: 0 Cov.: 30 AF XY: 0.0000268 AC XY: 15AN XY: 559744
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GnomAD4 genome ? AF: 0.000243 AC: 37AN: 151988Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25AN XY: 74330
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Luscan-Lumish syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 02, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been reported in one patient (12736.p1) with autism spectrum disorder and it was inherited from the patient's mother [PMID: 23160955] - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 12, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 25, 2019 | Variant summary: SETD2 c.19C>T (p.Gln7X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. Pathogenic loss-of-function variants in SETD2 have been reported in the literature (PMID: 26084711, 24852293). However, there is a second in-frame ATG codon (at Met 12) downstream from the variant of interest, with an appropriate context (i.e. Kozak consensus) for translational initiation that could generate an N-terminally truncated protein product (with the loss of 11 N-terminal amino acids). The variant allele was found at a frequency of 4.8e-05 in 125046 control chromosomes (gnomAD), predominantly reported in the Latino subpopulation with a frequency of 0.00054 (i.e. 5/9314 alleles). c.19C>T has been reported in the literature in an individual affected with autism spectrum disorder (ASD), however, this patient had normal nonverbal intelligence (with no information on head circumference), and also was noted to carry a de novo 16p11.2 duplication (O'Roak_2012). Therefore this report does not provide unequivocal conclusions about association of the variant with Luscan-Lumish syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) or uncertain significance (1x). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 08, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 21, 2020 | - - |
SETD2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 19, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
MutationTaster
Benign
A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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