Variant 18-63350985-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_002035.4(KDSR):c.512T>C(p.Val171Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000473 in 1,614,094 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00048 ( 2 hom. )

Consequence

KDSR
NM_002035.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDSR	NM_002035.4 linkuse as main transcript	c.512T>C	p.Val171Ala	missense_variant	6/10	ENST00000645214.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDSR	ENST00000645214.2 linkuse as main transcript	c.512T>C	p.Val171Ala	missense_variant	6/10		NM_002035.4	P1	Q06136-1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000374

AC:

AN:

251390

Hom.:

AF XY:

0.000331

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000712

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000482

AC:

704

AN:

1461842

Hom.:

Cov.:

AF XY:

0.000491

AC XY:

357

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000594

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000394

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000597

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000453

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 171 of the KDSR protein (p.Val171Ala). This variant is present in population databases (rs201014559, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with KDSR-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.066

BayesDel_noAF

Pathogenic

0.28

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;D;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

2.9

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

Polyphen

0.91

P;P;.

Vest4

0.88

MVP

0.93

MPC

0.86

ClinPred

0.19

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.87

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over