2-18560290-C-T

Variant names:

• chr2-18560290-C-T
• rs1411455434
• NM_020905.4:c.283G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020905.4(RDH14):​c.283G>A​(p.Ala95Thr) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RDH14 NM_020905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.707

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]

LOC105373456 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1023047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDH14	NM_020905.4	c.283G>A	p.Ala95Thr	missense_variant	Exon 1 of 2	ENST00000381249.4	NP_065956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDH14	ENST00000381249.4	c.283G>A	p.Ala95Thr	missense_variant	Exon 1 of 2	1	NM_020905.4	ENSP00000370648.3
NT5C1B-RDH14	ENST00000532967.5	c.1784+3555G>A		intron_variant	Intron 10 of 10	2		ENSP00000433415.1
NT5C1B-RDH14	ENST00000444297.2	c.1336-4482G>A		intron_variant	Intron 8 of 8	2		ENSP00000412639.2
RDH14	ENST00000468071.1	n.50+340G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000225 AC: 3 AN: 1332944 Hom.: 0 Cov.: 31 AF XY: 0.00000305 AC XY: 2 AN XY: 656710

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000339

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.45e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.283G>A (p.A95T) alteration is located in exon 1 (coding exon 1) of the RDH14 gene. This alteration results from a G to A substitution at nucleotide position 283, causing the alanine (A) at amino acid position 95 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	0.080
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.51	N
PROVEAN	Benign	0.17	N
REVEL	Benign	0.10
Sift	Benign	0.48	T
Sift4G	Benign	0.51	T
Polyphen		0.030	B
Vest4		0.047
MutPred		0.34		Gain of phosphorylation at A95 (P = 0.0475);
MVP		0.83
MPC		0.044
ClinPred		0.082	T
GERP RS		2.3
Varity_R		0.037
gMVP		0.21

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

Other links and lift over

dbSNP: rs1411455434; hg19: chr2-18741556;