rs3747610

chr16-4798188-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_024589.3(ROGDI):c.532-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,611,786 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: ROGDI NM_024589.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002144
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.64

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-4798188-C-T is Benign according to our data. Variant chr16-4798188-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 319403.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000269 (41/152278) while in subpopulation EAS AF= 0.00677 (35/5172). AF 95% confidence interval is 0.005. There are 1 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROGDI	NM_024589.3	c.532-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000322048.12
ROGDI	XM_006720947.5	c.532-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ROGDI	XM_047434636.1	c.262-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ROGDI	NR_046480.2	n.539-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROGDI	ENST00000322048.12	c.532-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_024589.3	P1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152162 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00675

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000533 AC: 130 AN: 243868 Hom.: 0 AF XY: 0.000505 AC XY: 67 AN XY: 132578

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00668

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.0000493

Gnomad NFE exome AF: 0.0000364

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000256 AC: 374 AN: 1459508 Hom.: 1 Cov.: 36 AF XY: 0.000240 AC XY: 174 AN XY: 726074

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00835

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152278 Hom.: 1 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74448

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00677

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000893 Hom.: 0

Bravo AF: 0.000268

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Amelocerebrohypohidrotic syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	ROGDI NM_024589.2 exon 8 c.532-4G>A: This variant has not been reported in the literature but is present in 0.6% (125/18632) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs3747610). This variant is present in ClinVar (Variation ID:319403). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Although this variant occurs in the splice region, computational prediction tools do not suggest that it may alter splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.079
Dann	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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: rs3747610; hg19: chr16-4848189;