rs1541296

Variant names:

• chr18-63354882-G-A
• rs1541296
• NM_002035.4:c.417+322C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002035.4(KDSR):​c.417+322C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 151,910 control chromosomes in the GnomAD database, including 27,999 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 0.60 (27999 hom., cov: 31)
• Consequence: KDSR NM_002035.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.593
• Publications: 14 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDSR	NM_002035.4	c.417+322C>T		intron_variant	Intron 5 of 9	ENST00000645214.2	NP_002026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDSR	ENST00000645214.2	c.417+322C>T		intron_variant	Intron 5 of 9		NM_002035.4	ENSP00000494352.1

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91385 AN: 151792 Hom.: 27992 Cov.: 31

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.613

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.602 AC: 91410 AN: 151910 Hom.: 27999 Cov.: 31 AF XY: 0.600 AC XY: 44555 AN XY: 74234

African (AFR) AF: 0.487 AC: 20184 AN: 41418

American (AMR) AF: 0.628 AC: 9584 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2083 AN: 3466

East Asian (EAS) AF: 0.468 AC: 2411 AN: 5152

South Asian (SAS) AF: 0.658 AC: 3166 AN: 4808

European-Finnish (FIN) AF: 0.645 AC: 6814 AN: 10568

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

European-Non Finnish (NFE) AF: 0.664 AC: 45100 AN: 67934

Other (OTH) AF: 0.608 AC: 1282 AN: 2110

Alfa AF: 0.639 Hom.: 50315

Bravo AF: 0.588

Asia WGS AF: 0.544 AC: 1891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	6.1
DANN	Benign	0.38
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1541296; hg19: chr18-61022115;