rs760386662
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS1_Supporting
The NM_018706.7(DHTKD1):c.1897-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_018706.7 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251448Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135896
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461802Hom.: 0 Cov.: 29 AF XY: 0.0000206 AC XY: 15AN XY: 727208
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74360
ClinVar
Submissions by phenotype
2-aminoadipic 2-oxoadipic aciduria Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 19, 2023 | Variant summary: DHTKD1 c.1897-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 3' acceptor site and one predicts the variant weakens the same canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 251448 control chromosomes (gnomAD). c.1897-1G>A has been reported in the literature in a heterozygous individual affected with Eosinophilic Esophagitis (Sherrill_2018). This report does not provide unequivocal conclusions about association of the variant with 2-Aminoadipic 2-Oxoadipic Aciduria. One publication reports experimental evidence evaluating mitochondrial function using fibroblasts from a heterozygous patient diagnosed with Eosinophilic Esophagitis (Sherrill_2018), however, this evidence does not allow convincing conclusions about the variant effect. The following publication has been ascertained in the context of this evaluation (PMID: 29669943). Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2023 | This sequence change affects an acceptor splice site in intron 10 of the DHTKD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DHTKD1 are known to be pathogenic (PMID: 23141293, 25860818). This variant is present in population databases (rs760386662, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with eosinophilic esophagitis (PMID: 29669943). ClinVar contains an entry for this variant (Variation ID: 467824). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects DHTKD1 function (PMID: 29669943). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Charcot-Marie-Tooth disease axonal type 2Q Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 03, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at