rs387907145

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024589.3(ROGDI):c.286C>T(p.Gln96*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,415,194 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ROGDI
NM_024589.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.67

Publications

6 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-4800548-G-A is Pathogenic according to our data. Variant chr16-4800548-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 31226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ROGDI	NM_024589.3 link	c.286C>T	p.Gln96*	stop_gained	Exon 5 of 11	ENST00000322048.12	NP_078865.1
ROGDI	XM_006720947.5 link	c.286C>T	p.Gln96*	stop_gained	Exon 5 of 11		XP_006721010.1
ROGDI	XM_047434636.1 link	c.16C>T	p.Gln6*	stop_gained	Exon 3 of 9		XP_047290592.1
ROGDI	NR_046480.2 link	n.293C>T		non_coding_transcript_exon_variant	Exon 4 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROGDI	ENST00000322048.12 link	c.286C>T	p.Gln96*	stop_gained	Exon 5 of 11	1	NM_024589.3	ENSP00000322832.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1415194

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32476

American (AMR)

AF:

0.00

AC:

AN:

37652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25296

East Asian (EAS)

AF:

0.00

AC:

AN:

37334

South Asian (SAS)

AF:

0.00

AC:

AN:

80416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000368

AC:

AN:

1087434

Other (OTH)

AF:

0.00

AC:

AN:

58678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amelocerebrohypohidrotic syndrome

Pathogenic:3

Dec 23, 2015

Undiagnosed Diseases Network, NIH

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 18, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ROGDI are known to be pathogenic (PMID: 22424600, 23086778). This variant has been observed in individual(s) with Kohlschutter-Tonz syndrome (PMID: 22424600). ClinVar contains an entry for this variant (Variation ID: 31226). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln96*) in the ROGDI gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

PhyloP100

9.7

Vest4

0.42

GERP RS

4.5

PromoterAI

-0.033

Neutral

(source)

Mutation Taster

=0/200

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over