rs371511979

Positions:

chr16-4797755-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_024589.3(ROGDI):c.781T>C(p.Phe261Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000334 in 1,557,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F261F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

ROGDI
NM_024589.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.31

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 Uncertain_significance. Variant got 0 ACMG points.

PM1

In a mutagenesis_site Decreased protein stability. (size 0) in uniprot entity ROGDI_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059770256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ROGDI	NM_024589.3 linkuse as main transcript	c.781T>C	p.Phe261Leu	missense_variant	10/11	ENST00000322048.12
ROGDI	XM_006720947.5 linkuse as main transcript	c.802T>C	p.Phe268Leu	missense_variant	10/11
ROGDI	XM_047434636.1 linkuse as main transcript	c.532T>C	p.Phe178Leu	missense_variant	8/9
ROGDI	NR_046480.2 linkuse as main transcript	n.788T>C		non_coding_transcript_exon_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROGDI	ENST00000322048.12 linkuse as main transcript	c.781T>C	p.Phe261Leu	missense_variant	10/11	1	NM_024589.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000142

AC:

AN:

120100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000448

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000178

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:

0.000620

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251256

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.000116

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000244

AC:

AN:

1437136

Hom.:

Cov.:

AF XY:

0.0000308

AC XY:

AN XY:

714796

show subpopulations

Gnomad4 AFR exome

AF:

0.000337

Gnomad4 AMR exome

AF:

0.000139

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:

0.0000119

Gnomad4 OTH exome

AF:

0.0000852

GnomAD4 genome

AF:

0.000141

AC:

AN:

120186

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

58638

show subpopulations

Gnomad4 AFR

AF:

0.000446

Gnomad4 AMR

AF:

0.000178

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:

0.000613

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Amelocerebrohypohidrotic syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2021

This sequence change replaces phenylalanine with leucine at codon 261 of the ROGDI protein (p.Phe261Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs371511979, ExAC 0.04%). This variant has not been reported in the literature in individuals affected with ROGDI-related conditions. 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 tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.049

T;T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.034

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.060

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.1

N;.;.

REVEL

Benign

0.15

Sift

Benign

0.86

T;.;.

Sift4G

Benign

1.0

T;.;.

Polyphen

0.0040

B;.;.

Vest4

0.47

MutPred

0.73

Loss of catalytic residue at F261 (P = 0.004);.;.;

MVP

0.12

MPC

0.023

ClinPred

0.10

GERP RS

5.1

Varity_R

0.49

gMVP

0.67

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