rs1060502981

Variant names:

• chr16-4801587-T-C
• rs1060502981
• NM_024589.3:c.118-2A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-4801587-T-C
• chr16-4801587-T-G

Variant summary

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

The NM_024589.3(ROGDI):​c.118-2A>G variant causes a splice acceptor, 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ROGDI NM_024589.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.43

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]

ENSG00000285952 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-4801587-T-C is Pathogenic according to our data. Variant chr16-4801587-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 410627.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROGDI	NM_024589.3	c.118-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 10	ENST00000322048.12	NP_078865.1
ROGDI	XM_006720947.5	c.118-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 10		XP_006721010.1
ROGDI	XM_047434636.1	c.-98-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 8		XP_047290592.1
ROGDI	NR_046480.2	n.180-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROGDI	ENST00000322048.12	c.118-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 10	1	NM_024589.3	ENSP00000322832.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amelocerebrohypohidrotic syndrome Pathogenic:1

Sep 01, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in ROGDI are known to be pathogenic (PMID: 22424600). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in individuals with a ROGDI-related disease. This sequence change affects an acceptor splice site in intron 2 of the ROGDI gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: -5
DS_AL_spliceai		1.0		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060502981; hg19: chr16-4851588;