rs371511979

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BP4_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. 13/22 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, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.31

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 -2 ACMG points.

PM1

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

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024589.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROGDI	NM_024589.3	MANE Select	c.781T>C	p.Phe261Leu	missense	Exon 10 of 11	NP_078865.1
	ROGDI	NR_046480.2		n.788T>C		non_coding_transcript_exon	Exon 9 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ROGDI	ENST00000322048.12	TSL:1 MANE Select	c.781T>C	p.Phe261Leu	missense	Exon 10 of 11	ENSP00000322832.6
ROGDI	ENST00000591392.5	TSL:3	c.709T>C	p.Phe237Leu	missense	Exon 9 of 9	ENSP00000467509.1
ROGDI	ENST00000586504.5	TSL:5	c.509T>C	p.Leu170Pro	missense	Exon 6 of 7	ENSP00000465076.1

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

GnomAD2 exomes

AF:

0.0000517

AC:

AN:

251256

AF XY:

0.0000515

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 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

African (AFR)

AF:

0.000337

AC:

AN:

32612

American (AMR)

AF:

0.000139

AC:

AN:

43270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25304

East Asian (EAS)

AF:

0.00

AC:

AN:

38552

South Asian (SAS)

AF:

0.00

AC:

AN:

85284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51714

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

1096082

Other (OTH)

AF:

0.0000852

AC:

AN:

58674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000141

AC:

AN:

120186

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

58638

show subpopulations

African (AFR)

AF:

0.000446

AC:

AN:

31364

American (AMR)

AF:

0.000178

AC:

AN:

11234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2858

East Asian (EAS)

AF:

0.00

AC:

AN:

4444

South Asian (SAS)

AF:

0.00

AC:

AN:

3732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

55490

Other (OTH)

AF:

0.000613

AC:

AN:

1630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000102

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.781T>C (p.F261L) alteration is located in exon 10 (coding exon 10) of the ROGDI gene. This alteration results from a T to C substitution at nucleotide position 781, causing the phenylalanine (F) at amino acid position 261 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Amelocerebrohypohidrotic syndrome

Uncertain:1

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.049

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.034

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.012

MetaRNN

Benign

0.060

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

6.3

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.1

REVEL

Benign

0.15

Sift

Benign

0.86

Sift4G

Benign

1.0

Polyphen

0.0040

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

Mutation Taster

=47/53

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over