rs3747610

Variant names:

• chr16-4798188-C-T
• rs3747610
• NM_024589.3:c.532-4G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_024589.3(ROGDI):​c.532-4G>A variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.00002144
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.64
• 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000285952 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 319403.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROGDI	NM_024589.3	c.532-4G>A		splice_region_variant, intron_variant	Intron 7 of 10	ENST00000322048.12	NP_078865.1
ROGDI	NR_046480.2	n.539-4G>A		splice_region_variant, intron_variant	Intron 6 of 9
ROGDI	XM_006720947.5	c.532-4G>A		splice_region_variant, intron_variant	Intron 7 of 10		XP_006721010.1
ROGDI	XM_047434636.1	c.262-4G>A		splice_region_variant, intron_variant	Intron 5 of 8		XP_047290592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROGDI	ENST00000322048.12	c.532-4G>A		splice_region_variant, intron_variant	Intron 7 of 10	1	NM_024589.3	ENSP00000322832.6

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

GnomAD2 exomes AF: 0.000533 AC: 130 AN: 243868 AF XY: 0.000505

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 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

African (AFR) AF: 0.0000897 AC: 3 AN: 33454

American (AMR) AF: 0.0000225 AC: 1 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00835 AC: 331 AN: 39622

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86050

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1110820

Other (OTH) AF: 0.000232 AC: 14 AN: 60234

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

African (AFR) AF: 0.0000481 AC: 2 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00677 AC: 35 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2114

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.079
DANN	Benign	0.62
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs3747610; hg19: chr16-4848189;