18-63355401-T-C

Variant names:

• chr18-63355401-T-C
• rs1809319
• NM_002035.4:c.321+97A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The NM_002035.4(KDSR):​c.321+97A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 1,604,996 control chromosomes in the GnomAD database, including 336,579 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.62 (29252 hom., cov: 32)
  • Exomes 𝑓: 0.65 (307327 hom.)
• Consequence: KDSR NM_002035.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.61
• Publications: 10 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: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

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.321+97A>G		intron	N/A	NP_002026.1	Q06136-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDSR	ENST00000645214.2	MANE Select	c.321+97A>G		intron	N/A	ENSP00000494352.1	Q06136-1
	KDSR	ENST00000951441.1		c.411+97A>G		intron	N/A	ENSP00000621500.1
	KDSR	ENST00000882920.1		c.411+97A>G		intron	N/A	ENSP00000552979.1

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93804 AN: 151972 Hom.: 29243 Cov.: 32

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.667

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.624

GnomAD4 exome AF: 0.649 AC: 943044 AN: 1452906 Hom.: 307327 Cov.: 34 AF XY: 0.650 AC XY: 469745 AN XY: 722508

African (AFR) AF: 0.538 AC: 17709 AN: 32912

American (AMR) AF: 0.618 AC: 26263 AN: 42488

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 15710 AN: 25840

East Asian (EAS) AF: 0.481 AC: 19052 AN: 39620

South Asian (SAS) AF: 0.674 AC: 56859 AN: 84314

European-Finnish (FIN) AF: 0.660 AC: 35151 AN: 53260

Middle Eastern (MID) AF: 0.609 AC: 3485 AN: 5722

European-Non Finnish (NFE) AF: 0.659 AC: 730865 AN: 1108704

Other (OTH) AF: 0.632 AC: 37950 AN: 60046

GnomAD4 genome AF: 0.617 AC: 93839 AN: 152090 Hom.: 29252 Cov.: 32 AF XY: 0.615 AC XY: 45728 AN XY: 74352

African (AFR) AF: 0.540 AC: 22420 AN: 41498

American (AMR) AF: 0.635 AC: 9703 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2086 AN: 3472

East Asian (EAS) AF: 0.469 AC: 2422 AN: 5168

South Asian (SAS) AF: 0.659 AC: 3179 AN: 4826

European-Finnish (FIN) AF: 0.645 AC: 6810 AN: 10560

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45120 AN: 67954

Other (OTH) AF: 0.619 AC: 1309 AN: 2116

Alfa AF: 0.633 Hom.: 37304

Bravo AF: 0.606

Asia WGS AF: 0.548 AC: 1908 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	12
DANN	Benign	0.65
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.61		Position offset: 1

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

Other links and lift over

dbSNP: rs1809319; hg19: chr18-61022634; COSMIC: COSV58506496; COSMIC: COSV58506496;