16-4797465-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024589.3(ROGDI):c.859T>C(p.Phe287Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000744 in 1,613,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

ROGDI
NM_024589.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 5.79

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)

ROGDI links:

ENSG00000285952 (HGNC:):

ENSG00000285952 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031229705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROGDI	NM_024589.3 link	c.859T>C	p.Phe287Leu	missense_variant	Exon 11 of 11	ENST00000322048.12	NP_078865.1	Q9GZN7
ROGDI	XM_006720947.5 link	c.880T>C	p.Phe294Leu	missense_variant	Exon 11 of 11		XP_006721010.1
ROGDI	XM_047434636.1 link	c.610T>C	p.Phe204Leu	missense_variant	Exon 9 of 9		XP_047290592.1
ROGDI	NR_046480.2 link	n.866T>C		non_coding_transcript_exon_variant	Exon 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROGDI	ENST00000322048.12 link	c.859T>C	p.Phe287Leu	missense_variant	Exon 11 of 11	1	NM_024589.3	ENSP00000322832.6		Q9GZN7

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000104

AC:

AN:

248996

AF XY:

0.0000667

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1460974

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726802

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33470

American (AMR)

AF:

0.0000448

AC:

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111514

Other (OTH)

AF:

0.0000829

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000342

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

41450

American (AMR)

AF:

0.000131

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.000450

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amelocerebrohypohidrotic syndrome

Uncertain:3

Sep 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 287 of the ROGDI protein (p.Phe287Leu). This variant is present in population databases (rs149138180, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ROGDI-related conditions. ClinVar contains an entry for this variant (Variation ID: 663148). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

May 27, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 11, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Uncertain:1

Jun 13, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ROGDI c.859T>C (p.Phe287Leu) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0001 in 248996 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ROGDI causing Amelocerebrohypohidrotic Syndrome, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.859T>C in individuals affected with Amelocerebrohypohidrotic Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 663148). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.859T>C (p.F287L) alteration is located in exon 11 (coding exon 11) of the ROGDI gene. This alteration results from a T to C substitution at nucleotide position 859, causing the phenylalanine (F) at amino acid position 287 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

Eigen

Benign

-0.17

Eigen_PC

Benign

0.016

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.015

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

PhyloP100

5.8

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.90

REVEL

Benign

0.18

Sift

Uncertain

0.013

Sift4G

Uncertain

0.038

Polyphen

0.0050

Vest4

0.11

MutPred

0.55

Gain of disorder (P = 0.2439);

MVP

0.29

MPC

0.027

ClinPred

0.092

GERP RS

4.3

Varity_R

0.11

gMVP

0.55

Mutation Taster

=84/16

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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16-4797465-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over