2-18555587-C-G

Variant names:

• chr2-18555587-C-G
• rs1558354949
• NM_020905.4:c.615G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020905.4(RDH14):​c.615G>C​(p.Leu205Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDH14 NM_020905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

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]

ACMG classification

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, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDH14	NM_020905.4	c.615G>C	p.Leu205Phe	missense_variant	Exon 2 of 2	ENST00000381249.4	NP_065956.1
NT5C1B-RDH14	NM_001199103.2	c.1557G>C	p.Leu519Phe	missense_variant	Exon 9 of 9		NP_001186032.1
NT5C1B-RDH14	NM_001199104.2	c.*197G>C		3_prime_UTR_variant	Exon 11 of 11		NP_001186033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDH14	ENST00000381249.4	c.615G>C	p.Leu205Phe	missense_variant	Exon 2 of 2	1	NM_020905.4	ENSP00000370648.3
NT5C1B-RDH14	ENST00000532967	c.*197G>C		3_prime_UTR_variant	Exon 11 of 11	2		ENSP00000433415.1
NT5C1B-RDH14	ENST00000444297.2	c.1557G>C	p.Leu519Phe	missense_variant	Exon 9 of 9	2		ENSP00000412639.2
RDH14	ENST00000468071.1	n.272G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.615G>C (p.L205F) alteration is located in exon 2 (coding exon 2) of the RDH14 gene. This alteration results from a G to C substitution at nucleotide position 615, causing the leucine (L) at amino acid position 205 to be replaced by a phenylalanine (F). 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	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.9	M;.
PROVEAN	Uncertain	-3.5	D;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.038	D;D
Polyphen		0.98	D;D
Vest4		0.68
MutPred		0.77		.;Loss of catalytic residue at L519 (P = 0.093);
MVP		1.0
MPC		0.17
ClinPred		0.92	D
GERP RS		1.9
Varity_R		0.20
gMVP		0.77

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: rs1558354949; hg19: chr2-18736853;