NM_001723.7:c.3370C>T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001723.7(DST):c.3370C>T(p.Gln1124*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,614,108 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 Pathogenic (★★).
Frequency
Consequence
NM_001723.7 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DST | ENST00000370765.11 | c.3370C>T | p.Gln1124* | stop_gained | Exon 23 of 24 | 1 | NM_001723.7 | ENSP00000359801.6 | ||
DST | ENST00000680361.1 | c.4929+3866C>T | intron_variant | Intron 36 of 103 | NM_001374736.1 | ENSP00000505098.1 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250682Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135492
GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461824Hom.: 0 Cov.: 34 AF XY: 0.0000481 AC XY: 35AN XY: 727206
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74456
ClinVar
Submissions by phenotype
Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Pathogenic:4
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not provided Pathogenic:2
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Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 27884173, 34426522, 30011071, 33471381, 35276021, 37431644, 37883475, 32802955, 37692655, 25059916, 20164846) -
Hereditary sensory and autonomic neuropathy type 6 Pathogenic:1Uncertain:1
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Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gln1124*) in the DST gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DST are known to be pathogenic (PMID: 22522446, 25059916, 30371979). This variant is present in population databases (rs201045495, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with epidermolysis bullosa simplex (PMID: 20164846, 25059916). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66012). 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. -
not specified Uncertain:1
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with epidermolysis bullosa simplex or hereditary sensory and autonomic neuropathy type VI - characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities. However, this variant is in the penultimate exon of one DST transcript and was identified in this individual's mother in the homozygous state. The proband is het for this variant.- Not consistant with phenotype and genereviews says 100% penetrance HMS -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at