rs143095485

chr16-4799725-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024589.3(ROGDI):c.393C>G(p.Asp131Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,613,742 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D131A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (82 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (70 hom.)
• Consequence: ROGDI NM_024589.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.609

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020662248).
• BP6: Variant 16-4799725-G-C is Benign according to our data. Variant chr16-4799725-G-C is described in ClinVar as [Benign]. Clinvar id is 261742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-4799725-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROGDI	NM_024589.3	c.393C>G	p.Asp131Glu	missense_variant	6/11	ENST00000322048.12
ROGDI	XM_006720947.5	c.393C>G	p.Asp131Glu	missense_variant	6/11
ROGDI	XM_047434636.1	c.123C>G	p.Asp41Glu	missense_variant	4/9
ROGDI	NR_046480.2	n.400C>G		non_coding_transcript_exon_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROGDI	ENST00000322048.12	c.393C>G	p.Asp131Glu	missense_variant	6/11	1	NM_024589.3	P1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2682 AN: 152120 Hom.: 82 Cov.: 33

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00464 AC: 1163 AN: 250636 Hom.: 27 AF XY: 0.00339 AC XY: 460 AN XY: 135560

Gnomad AFR exome AF: 0.0648

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00172 AC: 2511 AN: 1461504 Hom.: 70 Cov.: 31 AF XY: 0.00143 AC XY: 1041 AN XY: 727058

Gnomad4 AFR exome AF: 0.0631

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00333

GnomAD4 genome AF: 0.0177 AC: 2688 AN: 152238 Hom.: 82 Cov.: 33 AF XY: 0.0172 AC XY: 1281 AN XY: 74434

Gnomad4 AFR AF: 0.0614

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00269 Hom.: 8

Bravo AF: 0.0205

ESP6500AA AF: 0.0612 AC: 269

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00582 AC: 707

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amelocerebrohypohidrotic syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.034
Dann	Benign	0.88
DEOGEN2	Benign	0.041	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.77	T;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;.
MutationTaster	Benign	0.60	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N;.;.
REVEL	Benign	0.080
Sift	Benign	0.31	T;.;.
Sift4G	Benign	0.56	T;.;T
Polyphen		0.0030	B;.;.
Vest4		0.16
MutPred		0.76		Loss of helix (P = 0.0558);.;.;
MVP		0.048
MPC		0.023
ClinPred		0.0048	T
GERP RS		-9.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.26

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: rs143095485; hg19: chr16-4849726;