18-63362810-C-A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_002035.4(KDSR):c.167G>T(p.Gly56Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,264 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
KDSR
NM_002035.4 missense
NM_002035.4 missense
Scores
11
2
1
Clinical Significance
Conservation
PhyloP100: 7.42
Genes affected
KDSR (HGNC:4021): (3-ketodihydrosphingosine reductase) The protein encoded by this gene catalyzes the reduction of 3-ketodihydrosphingosine to dihydrosphingosine. The putative active site residues of the encoded protein are found on the cytosolic side of the endoplasmic reticulum membrane. A chromosomal rearrangement involving this gene is a cause of follicular lymphoma, also known as type II chronic lymphatic leukemia. The mutation of a conserved residue in the bovine ortholog causes spinal muscular atrophy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a topological_domain Cytoplasmic (size 244) in uniprot entity KDSR_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_002035.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.945
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KDSR | NM_002035.4 | c.167G>T | p.Gly56Val | missense_variant | 2/10 | ENST00000645214.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KDSR | ENST00000645214.2 | c.167G>T | p.Gly56Val | missense_variant | 2/10 | NM_002035.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251124Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135732
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461264Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2AN XY: 726962
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GnomAD4 genome ? Cov.: 32
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Cov.:
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 26, 2022 | The c.167G>T (p.G56V) alteration is located in exon 2 (coding exon 2) of the KDSR gene. This alteration results from a G to T substitution at nucleotide position 167, causing the glycine (G) at amino acid position 56 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;H;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
Polyphen
D;D;.;.;.
Vest4
1.0, 0.99
MVP
0.98
MPC
1.1
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