2-18555715-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_020905.4(RDH14):​c.487G>A​(p.Val163Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

RDH14
NM_020905.4 missense

Scores

10
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
RDH14 (HGNC:19979): (retinol dehydrogenase 14) Enables NADP-retinol dehydrogenase activity. Involved in osteoblast differentiation. Located in cytosol; endoplasmic reticulum; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]
NT5C1B-RDH14 (HGNC:38831): (NT5C1B-RDH14 readthrough) This locus represents naturally occurring read-through transcription between the neighboring NT5C1B (5'-nucleotidase, cytosolic IB) and RDH14 (retinol dehydrogenase 14) genes on chromosome 2. Alternative splicing results in multiple transcript variants, one of which encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Nov 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RDH14NM_020905.4 linkc.487G>A p.Val163Met missense_variant Exon 2 of 2 ENST00000381249.4 NP_065956.1 Q9HBH5Q53RX3
NT5C1B-RDH14NM_001199103.2 linkc.1429G>A p.Val477Met missense_variant Exon 9 of 9 NP_001186032.1
NT5C1B-RDH14NM_001199104.2 linkc.*69G>A 3_prime_UTR_variant Exon 11 of 11 NP_001186033.1 Q96P26-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RDH14ENST00000381249.4 linkc.487G>A p.Val163Met missense_variant Exon 2 of 2 1 NM_020905.4 ENSP00000370648.3 Q9HBH5
NT5C1B-RDH14ENST00000532967 linkc.*69G>A 3_prime_UTR_variant Exon 11 of 11 2 ENSP00000433415.1
NT5C1B-RDH14ENST00000444297.2 linkc.1429G>A p.Val477Met missense_variant Exon 9 of 9 2 ENSP00000412639.2 C9J2C7
RDH14ENST00000468071.1 linkn.144G>A non_coding_transcript_exon_variant Exon 2 of 2 2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 09, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.487G>A (p.V163M) alteration is located in exon 2 (coding exon 2) of the RDH14 gene. This alteration results from a G to A substitution at nucleotide position 487, causing the valine (V) at amino acid position 163 to be replaced by a methionine (M). 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
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.75
D;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Benign
0.076
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Uncertain
-0.17
T
MutationAssessor
Pathogenic
3.1
M;.
PROVEAN
Uncertain
-2.6
D;N
REVEL
Uncertain
0.58
Sift
Uncertain
0.0090
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.86
MutPred
0.81
.;Loss of catalytic residue at V477 (P = 0.0688);
MVP
0.56
MPC
0.29
ClinPred
0.98
D
GERP RS
5.5
Varity_R
0.25
gMVP
0.78

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: chr2-18736981; API