rs764899074

chr16-4801291-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024589.3(ROGDI):c.229_230del(p.Leu77AlafsTer64) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,710 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L77L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ROGDI NM_024589.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.58

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 12 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 16-4801291-CAG-C is Pathogenic according to our data. Variant chr16-4801291-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 31225.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-4801291-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROGDI	NM_024589.3	c.229_230del	p.Leu77AlafsTer64	frameshift_variant	4/11	ENST00000322048.12
ROGDI	XM_006720947.5	c.229_230del	p.Leu77AlafsTer64	frameshift_variant	4/11
ROGDI	XM_047434636.1	c.-16+210_-16+211del		intron_variant
ROGDI	NR_046480.2	n.262+210_262+211del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROGDI	ENST00000322048.12	c.229_230del	p.Leu77AlafsTer64	frameshift_variant	4/11	1	NM_024589.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000809 AC: 2 AN: 247168 Hom.: 0 AF XY: 0.00000748 AC XY: 1 AN XY: 133732

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.00

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: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456710 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 724010

Gnomad4 AFR exome AF: 0.0000299

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Amelocerebrohypohidrotic syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 02, 2021	This variant is present in population databases (rs764899074, ExAC 0.01%). This sequence change creates a premature translational stop signal (p.Leu77Alafs*64) in the ROGDI gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ROGDI are known to be pathogenic (PMID: 22424600, 23086778). This variant has been observed in individual(s) with Kohlschutter syndrome (PMID: 22424600). ClinVar contains an entry for this variant (Variation ID: 31225). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 06, 2012	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: -24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs764899074; hg19: chr16-4851292;