Genetic Variant NM_020905.4:c.328A>C (chr2-18560245-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020905.4(RDH14):c.328A>C(p.Ile110Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,371,550 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I110V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

RDH14
NM_020905.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.165

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

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=0.3395277).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RDH14	NM_020905.4	MANE Select	c.328A>C	p.Ile110Leu	missense	Exon 1 of 2	NP_065956.1	Q53RX3
NT5C1B-RDH14	NM_001199103.2		c.1336-4437A>C		intron	N/A	NP_001186032.1
NT5C1B-RDH14	NM_001199104.2		c.1784+3600A>C		intron	N/A	NP_001186033.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RDH14	ENST00000381249.4	TSL:1 MANE Select	c.328A>C	p.Ile110Leu	missense	Exon 1 of 2	ENSP00000370648.3	Q9HBH5
NT5C1B-RDH14	ENST00000532967.5	TSL:2	c.1784+3600A>C		intron	N/A	ENSP00000433415.1
RDH14	ENST00000870568.1		c.328A>C	p.Ile110Leu	missense	Exon 1 of 2	ENSP00000540627.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1371550

Hom.:

Cov.:

AF XY:

0.00000295

AC XY:

AN XY:

676856

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29690

American (AMR)

AF:

0.00

AC:

AN:

35162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24704

East Asian (EAS)

AF:

0.00

AC:

AN:

34080

South Asian (SAS)

AF:

0.0000253

AC:

AN:

78934

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4152

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074136

Other (OTH)

AF:

0.00

AC:

AN:

57300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.20

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.030

PhyloP100

0.17

PROVEAN

Benign

-1.1

REVEL

Benign

0.20

Sift

Benign

0.44

Sift4G

Benign

0.29

Polyphen

0.0010

Vest4

0.14

MutPred

0.46

Gain of disorder (P = 0.0446)

MVP

0.67

MPC

0.042

ClinPred

0.066

GERP RS

1.5

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.10

gMVP

0.32

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over