rs912095346

Variant names:

• chr2-18560277-G-A
• rs912095346
• NM_020905.4:c.296C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-18560277-G-A
• chr2-18560277-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020905.4(RDH14):​c.296C>T​(p.Pro99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000032 in 1,499,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P99R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: RDH14 NM_020905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.951
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09250212).

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.296C>T	p.Pro99Leu	missense	Exon 1 of 2	NP_065956.1	Q53RX3
	NT5C1B-RDH14	NM_001199103.2		c.1336-4469C>T		intron	N/A	NP_001186032.1
	NT5C1B-RDH14	NM_001199104.2		c.1784+3568C>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.296C>T	p.Pro99Leu	missense	Exon 1 of 2	ENSP00000370648.3	Q9HBH5
	NT5C1B-RDH14	ENST00000532967.5	TSL:2	c.1784+3568C>T		intron	N/A	ENSP00000433415.1
	RDH14	ENST00000870568.1		c.296C>T	p.Pro99Leu	missense	Exon 1 of 2	ENSP00000540627.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000319 AC: 43 AN: 1347844 Hom.: 0 Cov.: 31 AF XY: 0.0000301 AC XY: 20 AN XY: 664464

African (AFR) AF: 0.0000365 AC: 1 AN: 27388

American (AMR) AF: 0.00 AC: 0 AN: 31372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23936

East Asian (EAS) AF: 0.00 AC: 0 AN: 30762

South Asian (SAS) AF: 0.00 AC: 0 AN: 76562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4050

European-Non Finnish (NFE) AF: 0.0000395 AC: 42 AN: 1064414

Other (OTH) AF: 0.00 AC: 0 AN: 56190

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

African (AFR) AF: 0.0000724 AC: 3 AN: 41452

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: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.7
DANN	Benign	0.83
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.61	N
PhyloP100		-0.95
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.12
Sift	Benign	0.054	T
Sift4G	Uncertain	0.043	D
Polyphen		0.0	B
Vest4		0.077
MutPred		0.32		Loss of glycosylation at P99 (P = 0.0593)
MVP		0.57
MPC		0.042
ClinPred		0.058	T
GERP RS		0.99
PromoterAI		0.28	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.048
gMVP		0.27
Mutation Taster		=96/4	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: rs912095346; hg19: chr2-18741543;