2-18560428-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020905.4(RDH14):​c.145A>G​(p.Thr49Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000245 in 1,505,182 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

RDH14
NM_020905.4 missense

Scores

8
9
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.76
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RDH14NM_020905.4 linkc.145A>G p.Thr49Ala missense_variant Exon 1 of 2 ENST00000381249.4 NP_065956.1 Q9HBH5Q53RX3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RDH14ENST00000381249.4 linkc.145A>G p.Thr49Ala missense_variant Exon 1 of 2 1 NM_020905.4 ENSP00000370648.3 Q9HBH5
NT5C1B-RDH14ENST00000532967.5 linkc.1784+3417A>G intron_variant Intron 10 of 10 2 ENSP00000433415.1
NT5C1B-RDH14ENST00000444297.2 linkc.1336-4620A>G intron_variant Intron 8 of 8 2 ENSP00000412639.2 C9J2C7
RDH14ENST00000468071.1 linkn.50+202A>G intron_variant Intron 1 of 1 2

Frequencies

GnomAD3 genomes
AF:
0.000217
AC:
33
AN:
152056
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000368
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000171
AC:
17
AN:
99596
Hom.:
0
AF XY:
0.000160
AC XY:
9
AN XY:
56114
show subpopulations
Gnomad AFR exome
AF:
0.000603
Gnomad AMR exome
AF:
0.0000500
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000347
Gnomad OTH exome
AF:
0.000676
GnomAD4 exome
AF:
0.000248
AC:
336
AN:
1353126
Hom.:
0
Cov.:
31
AF XY:
0.000205
AC XY:
137
AN XY:
667706
show subpopulations
Gnomad4 AFR exome
AF:
0.0000363
Gnomad4 AMR exome
AF:
0.0000315
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000180
Gnomad4 NFE exome
AF:
0.000297
Gnomad4 OTH exome
AF:
0.000195
GnomAD4 genome
AF:
0.000217
AC:
33
AN:
152056
Hom.:
0
Cov.:
32
AF XY:
0.000283
AC XY:
21
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.000368
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000270
Hom.:
0
Bravo
AF:
0.000185
ExAC
AF:
0.0000804
AC:
7

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
May 20, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.145A>G (p.T49A) alteration is located in exon 1 (coding exon 1) of the RDH14 gene. This alteration results from a A to G substitution at nucleotide position 145, causing the threonine (T) at amino acid position 49 to be replaced by an alanine (A). 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
0.93
BayesDel_addAF
Uncertain
0.049
T
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D
Eigen
Pathogenic
0.79
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.71
D
MetaRNN
Uncertain
0.58
D
MetaSVM
Uncertain
0.016
D
MutationAssessor
Uncertain
2.8
M
PROVEAN
Uncertain
-4.2
D
REVEL
Uncertain
0.61
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.88
MVP
0.72
MPC
0.29
ClinPred
0.22
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.70
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

LitVar

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

Other links and lift over

dbSNP: rs767202026; hg19: chr2-18741694; API