chr16-4797465-A-G

Position:

chr16-4797465-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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:4

Conservation

PhyloP100: 5.79

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ROGDI	NM_024589.3 linkuse as main transcript	c.859T>C	p.Phe287Leu	missense_variant	11/11	ENST00000322048.12
ROGDI	XM_006720947.5 linkuse as main transcript	c.880T>C	p.Phe294Leu	missense_variant	11/11
ROGDI	XM_047434636.1 linkuse as main transcript	c.610T>C	p.Phe204Leu	missense_variant	9/9
ROGDI	NR_046480.2 linkuse as main transcript	n.866T>C		non_coding_transcript_exon_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROGDI	ENST00000322048.12 linkuse as main transcript	c.859T>C	p.Phe287Leu	missense_variant	11/11	1	NM_024589.3	P1

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

GnomAD3 exomes

AF:

0.000104

AC:

AN:

248996

Hom.:

AF XY:

0.0000667

AC XY:

AN XY:

134876

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 SAS 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

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.000342

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00121

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000552

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amelocerebrohypohidrotic syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 07, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 27, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 11, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2021

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

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

MutationTaster

Benign

0.67

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over