chr16-4799704-C-T

Position:

• chr16-4799704-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000322048.12(ROGDI):​c.414G>A​(p.Thr138=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,612,418 control chromosomes in the GnomAD database, including 16,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1153 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15370 hom.)
• Consequence: ROGDI ENST00000322048.12 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.74

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-4799704-C-T is Benign according to our data. Variant chr16-4799704-C-T is described in ClinVar as [Benign]. Clinvar id is 130160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROGDI	NM_024589.3	c.414G>A	p.Thr138=	synonymous_variant	6/11	ENST00000322048.12	NP_078865.1
ROGDI	XM_006720947.5	c.414G>A	p.Thr138=	synonymous_variant	6/11		XP_006721010.1
ROGDI	XM_047434636.1	c.144G>A	p.Thr48=	synonymous_variant	4/9		XP_047290592.1
ROGDI	NR_046480.2	n.421G>A		non_coding_transcript_exon_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROGDI	ENST00000322048.12	c.414G>A	p.Thr138=	synonymous_variant	6/11	1	NM_024589.3	ENSP00000322832	P1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16660 AN: 152090 Hom.: 1159 Cov.: 33

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.0360

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.130 AC: 32330 AN: 249506 Hom.: 2584 AF XY: 0.137 AC XY: 18503 AN XY: 134952

Gnomad AFR exome AF: 0.0327

Gnomad AMR exome AF: 0.0779

Gnomad ASJ exome AF: 0.249

Gnomad EAS exome AF: 0.0299

Gnomad SAS exome AF: 0.209

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.140 AC: 204537 AN: 1460210 Hom.: 15370 Cov.: 31 AF XY: 0.143 AC XY: 103590 AN XY: 726400

Gnomad4 AFR exome AF: 0.0334

Gnomad4 AMR exome AF: 0.0832

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.0521

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.109 AC: 16633 AN: 152208 Hom.: 1153 Cov.: 33 AF XY: 0.109 AC XY: 8093 AN XY: 74418

Gnomad4 AFR AF: 0.0385

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.243

Gnomad4 EAS AF: 0.0359

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.132

Alfa AF: 0.138 Hom.: 1349

Bravo AF: 0.104

Asia WGS AF: 0.127 AC: 441 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Amelocerebrohypohidrotic syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.064
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs11553876; hg19: chr16-4849705; COSMIC: COSV58927157; COSMIC: COSV58927157;