rs1114167451

Variant names:

• chr18-63355565-T-G
• rs1114167451
• NM_002035.4:c.256-2A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

The NM_002035.4(KDSR):​c.256-2A>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000495 in 1,415,512 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: KDSR NM_002035.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.99
• Publications: 0 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, Genomics England PanelApp, G2P
• erythrokeratodermia variabilis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.066066064 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.3, offset of 19, new splice context is: ggtggtgctttgcatatcAGttg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 18-63355565-T-G is Pathogenic according to our data. Variant chr18-63355565-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 427790.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDSR	NM_002035.4	c.256-2A>C		splice_acceptor_variant, intron_variant	Intron 3 of 9	ENST00000645214.2	NP_002026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDSR	ENST00000645214.2	c.256-2A>C		splice_acceptor_variant, intron_variant	Intron 3 of 9		NM_002035.4	ENSP00000494352.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000495 AC: 7 AN: 1415512 Hom.: 0 Cov.: 32 AF XY: 0.00000427 AC XY: 3 AN XY: 702968

African (AFR) AF: 0.00 AC: 0 AN: 30732

American (AMR) AF: 0.00 AC: 0 AN: 30552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23406

East Asian (EAS) AF: 0.00 AC: 0 AN: 39086

South Asian (SAS) AF: 0.00 AC: 0 AN: 78784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 0.00000638 AC: 7 AN: 1097216

Other (OTH) AF: 0.00 AC: 0 AN: 58192

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Erythrokeratodermia variabilis et progressiva 4 Pathogenic:1

Jun 13, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.0	.;.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.;.
PhyloP100		8.0
PROVEAN	Benign	0.0	.;.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.
Vest4		0.0
GERP RS		5.5
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: -2

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

Other links and lift over

dbSNP: rs1114167451; hg19: chr18-61022798;