2-18560294-C-A

Variant names:

• chr2-18560294-C-A
• rs1161760076
• NM_020905.4:c.279G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020905.4(RDH14):​c.279G>T​(p.Gln93His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000405 in 1,482,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: RDH14 NM_020905.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.55
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3418004).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020905.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH14	NM_020905.4	MANE Select	c.279G>T	p.Gln93His	missense	Exon 1 of 2	NP_065956.1	Q53RX3
	NT5C1B-RDH14	NM_001199103.2		c.1336-4486G>T		intron	N/A	NP_001186032.1
	NT5C1B-RDH14	NM_001199104.2		c.1784+3551G>T		intron	N/A	NP_001186033.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH14	ENST00000381249.4	TSL:1 MANE Select	c.279G>T	p.Gln93His	missense	Exon 1 of 2	ENSP00000370648.3	Q9HBH5
	NT5C1B-RDH14	ENST00000532967.5	TSL:2	c.1784+3551G>T		intron	N/A	ENSP00000433415.1
	RDH14	ENST00000870568.1		c.279G>T	p.Gln93His	missense	Exon 1 of 2	ENSP00000540627.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000376 AC: 5 AN: 1330632 Hom.: 0 Cov.: 31 AF XY: 0.00000610 AC XY: 4 AN XY: 655418

African (AFR) AF: 0.00 AC: 0 AN: 26662

American (AMR) AF: 0.00 AC: 0 AN: 27490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23198

East Asian (EAS) AF: 0.00 AC: 0 AN: 29374

South Asian (SAS) AF: 0.00 AC: 0 AN: 74084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4008

European-Non Finnish (NFE) AF: 0.00000473 AC: 5 AN: 1057660

Other (OTH) AF: 0.00 AC: 0 AN: 55282

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.88	L
PhyloP100		1.6
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.10
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.046	D
Polyphen		0.26	B
Vest4		0.10
MutPred		0.36		Loss of MoRF binding (P = 0.1044)
MVP		0.93
MPC		0.074
ClinPred		0.46	T
GERP RS		3.4
PromoterAI		0.059	Neutral
Varity_R		0.17
gMVP		0.31
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs1161760076; hg19: chr2-18741560;