Genetic Variant RDH14:p.Thr49Ala (chr2-18560428-T-C) – ACMG Classification: Uncertain_significance (2 pts)

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

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]

RDH14 links:

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]

NT5C1B-RDH14 links:

LOC105373456 (HGNC:):

LOC105373456 links:

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
RDH14	NM_020905.4 link	c.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	UniProt
RDH14	ENST00000381249.4 link	c.145A>G	p.Thr49Ala	missense_variant	Exon 1 of 2	1	NM_020905.4	ENSP00000370648.3	Q9HBH5
NT5C1B-RDH14	ENST00000532967.5 link	c.1784+3417A>G		intron_variant	Intron 10 of 10	2		ENSP00000433415.1
NT5C1B-RDH14	ENST00000444297.2 link	c.1336-4620A>G		intron_variant	Intron 8 of 8	2		ENSP00000412639.2	C9J2C7
RDH14	ENST00000468071.1 link	n.50+202A>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152056

Hom.:

Cov.:

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:

AN:

99596

Hom.:

AF XY:

0.000160

AC XY:

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.:

Cov.:

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:

AN:

152056

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

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.:

Bravo

AF:

0.000185

ExAC

AF:

0.0000804

AC:

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

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.58

MetaSVM

Uncertain

0.016

MutationAssessor

Uncertain

2.8

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.88

MVP

0.72

MPC

0.29

ClinPred

0.22

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.

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