18-63331816-C-G

Position:

• chr18-63331816-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002035.4(KDSR):​c.965G>C​(p.Arg322Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDSR NM_002035.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35385185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDSR	NM_002035.4	c.965G>C	p.Arg322Thr	missense_variant	10/10	ENST00000645214.2	NP_002026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDSR	ENST00000645214.2	c.965G>C	p.Arg322Thr	missense_variant	10/10		NM_002035.4	ENSP00000494352.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

The c.965G>C (p.R322T) alteration is located in exon 10 (coding exon 10) of the KDSR gene. This alteration results from a G to C substitution at nucleotide position 965, causing the arginine (R) at amino acid position 322 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T;T;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.2	M;M;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.1	.;D;.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	.;D;.;D
Sift4G	Uncertain	0.0090	.;D;.;D
Polyphen		0.79	P;P;.;.
Vest4		0.37, 0.35
MutPred		0.42		Gain of glycosylation at R322 (P = 0.0515);Gain of glycosylation at R322 (P = 0.0515);.;.;
MVP		0.96
MPC		0.54
ClinPred		0.97	D
GERP RS		2.1
Varity_R		0.27
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-60999049;