chr2-18560458-C-CG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_020905.4(RDH14):​c.114dupC​(p.Gly39ArgfsTer97) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000634 in 1,513,300 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

RDH14
NM_020905.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -0.0850

Publications

1 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]
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-18560458-C-CG is Pathogenic according to our data. Variant chr2-18560458-C-CG is described in CliVar as Likely_pathogenic. Clinvar id is 827760.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-18560458-C-CG is described in CliVar as Likely_pathogenic. Clinvar id is 827760.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-18560458-C-CG is described in CliVar as Likely_pathogenic. Clinvar id is 827760.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-18560458-C-CG is described in CliVar as Likely_pathogenic. Clinvar id is 827760.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-18560458-C-CG is described in CliVar as Likely_pathogenic. Clinvar id is 827760.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-18560458-C-CG is described in CliVar as Likely_pathogenic. Clinvar id is 827760.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-18560458-C-CG is described in CliVar as Likely_pathogenic. Clinvar id is 827760.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-18560458-C-CG is described in CliVar as Likely_pathogenic. Clinvar id is 827760.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RDH14NM_020905.4 linkc.114dupC p.Gly39ArgfsTer97 frameshift_variant Exon 1 of 2 ENST00000381249.4 NP_065956.1 Q9HBH5Q53RX3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RDH14ENST00000381249.4 linkc.114dupC p.Gly39ArgfsTer97 frameshift_variant Exon 1 of 2 1 NM_020905.4 ENSP00000370648.3 Q9HBH5
NT5C1B-RDH14ENST00000532967.5 linkc.1784+3386dupC intron_variant Intron 10 of 10 2 ENSP00000433415.1
NT5C1B-RDH14ENST00000444297.2 linkc.1336-4651dupC intron_variant Intron 8 of 8 2 ENSP00000412639.2 C9J2C7
RDH14ENST00000468071.1 linkn.50+171dupC intron_variant Intron 1 of 1 2

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152162
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.000103
AC:
11
AN:
106904
AF XY:
0.000101
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000386
Gnomad NFE exome
AF:
0.0000757
Gnomad OTH exome
AF:
0.000300
GnomAD4 exome
AF:
0.0000610
AC:
83
AN:
1361032
Hom.:
0
Cov.:
31
AF XY:
0.0000611
AC XY:
41
AN XY:
671580
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
28116
American (AMR)
AF:
0.0000298
AC:
1
AN:
33506
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24232
East Asian (EAS)
AF:
0.00
AC:
0
AN:
32666
South Asian (SAS)
AF:
0.000129
AC:
10
AN:
77246
European-Finnish (FIN)
AF:
0.000660
AC:
22
AN:
33330
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4170
European-Non Finnish (NFE)
AF:
0.0000420
AC:
45
AN:
1070952
Other (OTH)
AF:
0.0000880
AC:
5
AN:
56814
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
5
11
16
22
27
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152268
Hom.:
0
Cov.:
33
AF XY:
0.0000940
AC XY:
7
AN XY:
74442
show subpopulations
African (AFR)
AF:
0.0000722
AC:
3
AN:
41574
American (AMR)
AF:
0.0000653
AC:
1
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.000194
AC:
1
AN:
5152
South Asian (SAS)
AF:
0.000414
AC:
2
AN:
4828
European-Finnish (FIN)
AF:
0.000188
AC:
2
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
68002
Other (OTH)
AF:
0.000473
AC:
1
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.517
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000189

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Cerebellar atrophy;C3714756:Intellectual disability Pathogenic:1
Mar 03, 2020
Molecular Neuropsychiatry & Development Lab, Centre for Addiction and Mental Health
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:research

The NM_020905.3:c.114dup/ Gly39Argfs*97 biallelic variant in RDH14 is reported segregating in two affected members of a single large family from Pakistan (Pastore et al, submitted). The variant is predicted to lead to premature truncation of the protein with loss of function, along with nonsense-mediated mRNA decay. No corroborative evidence from other families, or from animal models is available as yet, and thus there remain reservations as to the pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
-0.085
Mutation Taster
=59/141
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs779464218; hg19: chr2-18741724; API