rs376868221

Positions:

chr16-4797706-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_024589.3(ROGDI):c.822+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,225,456 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0014 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

ROGDI
NM_024589.3 splice_region, intron

Scores

Splicing: ADA: 0.0001912

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -3.03

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01217407).

BP6

Variant 16-4797706-G-A is Benign according to our data. Variant chr16-4797706-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 416250.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00144 (64/44408) while in subpopulation AFR AF= 0.00644 (63/9784). AF 95% confidence interval is 0.00516. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
ROGDI	NM_024589.3 linkuse as main transcript	c.822+8C>T	splice_region_variant, intron_variant	ENST00000322048.12	NP_078865.1
ROGDI	XM_006720947.5 linkuse as main transcript	c.843+8C>T	splice_region_variant, intron_variant		XP_006721010.1
ROGDI	XM_047434636.1 linkuse as main transcript	c.573+8C>T	splice_region_variant, intron_variant		XP_047290592.1
ROGDI	NR_046480.2 linkuse as main transcript	n.829+8C>T	splice_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROGDI	ENST00000322048.12 linkuse as main transcript	c.822+8C>T		splice_region_variant, intron_variant		1	NM_024589.3	ENSP00000322832	P1

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

AN:

44408

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00644

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000472

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000120

AC:

AN:

225584

Hom.:

AF XY:

0.0000974

AC XY:

AN XY:

123262

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000360

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000290

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000516

AC:

AN:

1181048

Hom.:

Cov.:

AF XY:

0.0000465

AC XY:

AN XY:

580438

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000419

Gnomad4 SAS exome

AF:

0.0000169

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000691

GnomAD4 genome

AF:

0.00144

AC:

AN:

44408

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

AN XY:

22012

show subpopulations

Gnomad4 AFR

AF:

0.00644

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000472

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000350

Hom.:

Bravo

AF:

0.000491

ESP6500AA

AF:

0.00228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Amelocerebrohypohidrotic syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 18, 2022	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.2% (34/16696) (https://gnomad.broadinstitute.org/variant/16-4847707-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:416250). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Splice prediction tools do not suggest that this variant may affect 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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

ROGDI-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.061

DANN

Benign

0.48

DEOGEN2

Benign

0.0056

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.29

MetaRNN

Benign

0.012

MutationTaster

Benign

1.0

MVP

0.15

GERP RS

-6.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over