NM_024589.3:c.117+1G>T

Variant names:

• chr16-4802381-C-A
• rs570952151
• NM_024589.3:c.117+1G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_024589.3(ROGDI):​c.117+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ROGDI NM_024589.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.38
• Publications: 1 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: PanelApp Australia, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.083333336 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-4802381-C-A is Pathogenic according to our data. Variant chr16-4802381-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 947711.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROGDI	NM_024589.3	MANE Select	c.117+1G>T		splice_donor intron	N/A	NP_078865.1	Q9GZN7
	ROGDI	NR_046480.2		n.179+1G>T		splice_donor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROGDI	ENST00000322048.12	TSL:1 MANE Select	c.117+1G>T		splice_donor intron	N/A	ENSP00000322832.6	Q9GZN7
	ROGDI	ENST00000907806.1		c.117+1G>T		splice_donor intron	N/A	ENSP00000577865.1
	ROGDI	ENST00000912071.1		c.117+1G>T		splice_donor intron	N/A	ENSP00000582130.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1418102 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 703586

African (AFR) AF: 0.00 AC: 0 AN: 31758

American (AMR) AF: 0.00 AC: 0 AN: 38086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24636

East Asian (EAS) AF: 0.00 AC: 0 AN: 37502

South Asian (SAS) AF: 0.00 AC: 0 AN: 80706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094322

Other (OTH) AF: 0.00 AC: 0 AN: 58500

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Amelocerebrohypohidrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.4
GERP RS		4.3
PromoterAI		-0.098	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 2
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs570952151; hg19: chr16-4852382;