16-4798592-CG-CGGG

Variant names:

• chr16-4798592-C-CGG
• rs786205124
• NM_024589.3:c.506_507dupCC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024589.3(ROGDI):​c.506_507dupCC​(p.Glu170ProfsTer73) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,416,344 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P169P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ROGDI NM_024589.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -2.60
• Publications: 2 publications found

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)

ENSG00000285952 (HGNC:):

ACMG classification

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 16-4798592-C-CGG is Pathogenic according to our data. Variant chr16-4798592-C-CGG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 453294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROGDI	NM_024589.3	c.506_507dupCC	p.Glu170ProfsTer73	frameshift_variant	Exon 7 of 11	ENST00000322048.12	NP_078865.1
ROGDI	XM_006720947.5	c.506_507dupCC	p.Glu170ProfsTer80	frameshift_variant	Exon 7 of 11		XP_006721010.1
ROGDI	XM_047434636.1	c.236_237dupCC	p.Glu80ProfsTer80	frameshift_variant	Exon 5 of 9		XP_047290592.1
ROGDI	NR_046480.2	n.513_514dupCC		non_coding_transcript_exon_variant	Exon 6 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROGDI	ENST00000322048.12	c.506_507dupCC	p.Glu170ProfsTer73	frameshift_variant	Exon 7 of 11	1	NM_024589.3	ENSP00000322832.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 185362 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000148 AC: 21 AN: 1416344 Hom.: 0 Cov.: 31 AF XY: 0.0000185 AC XY: 13 AN XY: 701424

African (AFR) AF: 0.0000302 AC: 1 AN: 33150

American (AMR) AF: 0.00 AC: 0 AN: 37226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25228

East Asian (EAS) AF: 0.00 AC: 0 AN: 38606

South Asian (SAS) AF: 0.00 AC: 0 AN: 81024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.0000174 AC: 19 AN: 1094880

Other (OTH) AF: 0.0000169 AC: 1 AN: 59064

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amelocerebrohypohidrotic syndrome Pathogenic:3

Nov 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2015

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu170Profs*73) 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 is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ROGDI-related conditions. ClinVar contains an entry for this variant (Variation ID: 453294). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.6
Mutation Taster		=7/193	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs786205124; hg19: chr16-4848593;