rs387907145

chr16-4800548-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024589.3(ROGDI):c.286C>T(p.Gln96Ter) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.67

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 31226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-4800548-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROGDI	NM_024589.3	c.286C>T	p.Gln96Ter	stop_gained	5/11	ENST00000322048.12
ROGDI	XM_006720947.5	c.286C>T	p.Gln96Ter	stop_gained	5/11
ROGDI	XM_047434636.1	c.16C>T	p.Gln6Ter	stop_gained	3/9
ROGDI	NR_046480.2	n.293C>T		non_coding_transcript_exon_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROGDI	ENST00000322048.12	c.286C>T	p.Gln96Ter	stop_gained	5/11	1	NM_024589.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000283 AC: 4 AN: 1415194 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 699328

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000368

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amelocerebrohypohidrotic syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Dec 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2020	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2006	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	42
Dann	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A
Vest4		0.42
GERP RS		4.5

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

Other links and lift over

dbSNP: rs387907145; hg19: chr16-4850549;