16-4802386-A-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024589.3(ROGDI):​c.113T>G​(p.Leu38Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000211 in 1,418,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L38V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ROGDI
NM_024589.3 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.89

Publications

0 publications found
Variant links:
Genes affected
ROGDI (HGNC:29478): (rogdi atypical leucine zipper) Involved in brain development; neurogenesis; and odontogenesis of dentin-containing tooth. Located in nuclear envelope. Implicated in Kohlschutter-Tonz syndrome. [provided by Alliance of Genome Resources, Apr 2022]
ROGDI Gene-Disease associations (from GenCC):
  • amelocerebrohypohidrotic syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ROGDINM_024589.3 linkc.113T>G p.Leu38Arg missense_variant Exon 2 of 11 ENST00000322048.12 NP_078865.1 Q9GZN7
ROGDIXM_006720947.5 linkc.113T>G p.Leu38Arg missense_variant Exon 2 of 11 XP_006721010.1
ROGDINR_046480.2 linkn.175T>G non_coding_transcript_exon_variant Exon 2 of 10
ROGDIXM_047434636.1 linkc.-103T>G 5_prime_UTR_variant Exon 1 of 9 XP_047290592.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ROGDIENST00000322048.12 linkc.113T>G p.Leu38Arg missense_variant Exon 2 of 11 1 NM_024589.3 ENSP00000322832.6 Q9GZN7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000211
AC:
3
AN:
1418598
Hom.:
0
Cov.:
31
AF XY:
0.00000284
AC XY:
2
AN XY:
703980
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31762
American (AMR)
AF:
0.00
AC:
0
AN:
38158
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24618
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37462
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80830
European-Finnish (FIN)
AF:
0.0000425
AC:
2
AN:
47110
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5592
European-Non Finnish (NFE)
AF:
9.14e-7
AC:
1
AN:
1094534
Other (OTH)
AF:
0.00
AC:
0
AN:
58532
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Amelocerebrohypohidrotic syndrome Uncertain:1
Jan 27, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ROGDI-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces leucine with arginine at codon 38 of the ROGDI protein (p.Leu38Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
T;T
Eigen
Uncertain
0.68
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Uncertain
-0.022
T
MutationAssessor
Uncertain
2.5
M;.
PhyloP100
6.9
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-5.6
D;.
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0010
D;.
Polyphen
1.0
D;.
Vest4
0.96
MutPred
0.91
Loss of stability (P = 0.0166);Loss of stability (P = 0.0166);
MVP
0.44
MPC
0.20
ClinPred
1.0
D
GERP RS
4.4
PromoterAI
0.091
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.87

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: rs1555491894; hg19: chr16-4852387; API