18-63335257-C-T

Variant names:

• chr18-63335257-C-T
• rs752611378
• NM_002035.4:c.879G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3 PP5_Very_Strong BP4

The NM_002035.4(KDSR):​c.879G>A​(p.Gln293Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000647 in 1,607,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005417638: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV006325930: RNA studies of c.879G>A showed complete skipping of exon 9 resulting in a shortened in-frame transcript (PMID:28575652)".

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: KDSR NM_002035.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.5912
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.12
• Publications: 2 publications found

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]

KDSR Gene-Disease associations (from GenCC):

• erythrokeratodermia variabilis et progressiva 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp
• erythrokeratodermia variabilis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005417638: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV006325930: RNA studies of c.879G>A showed complete skipping of exon 9 resulting in a shortened in-frame transcript (PMID: 28575652)
• PP5: Variant 18-63335257-C-T is Pathogenic according to our data. Variant chr18-63335257-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 427791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002035.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDSR	NM_002035.4	MANE Select	c.879G>A	p.Gln293Gln	splice_region synonymous	Exon 9 of 10	NP_002026.1	Q06136-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDSR	ENST00000645214.2	MANE Select	c.879G>A	p.Gln293Gln	splice_region synonymous	Exon 9 of 10	ENSP00000494352.1	Q06136-1
	KDSR	ENST00000951441.1		c.969G>A	p.Gln323Gln	splice_region synonymous	Exon 10 of 11	ENSP00000621500.1
	KDSR	ENST00000882920.1		c.885G>A	p.Gln295Gln	splice_region synonymous	Exon 9 of 10	ENSP00000552979.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250812 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000687 AC: 100 AN: 1455310 Hom.: 0 Cov.: 28 AF XY: 0.0000663 AC XY: 48 AN XY: 724478

African (AFR) AF: 0.0000300 AC: 1 AN: 33324

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.0000832 AC: 92 AN: 1106178

Other (OTH) AF: 0.0000166 AC: 1 AN: 60164

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Erythrokeratodermia variabilis et progressiva 4 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		6.1
Mutation Taster		=37/63	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.59
dbscSNV1_RF	Benign	0.46
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752611378; hg19: chr18-61002490;