16-4797966-C-T

Position:

chr16-4797966-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_024589.3(ROGDI):c.667G>A(p.Ala223Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000579 in 1,606,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A223S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

ROGDI
NM_024589.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:1

Conservation

PhyloP100: 1.85

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27486086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ROGDI	NM_024589.3 linkuse as main transcript	c.667G>A	p.Ala223Thr	missense_variant	9/11	ENST00000322048.12
ROGDI	XM_006720947.5 linkuse as main transcript	c.667G>A	p.Ala223Thr	missense_variant	9/11
ROGDI	XM_047434636.1 linkuse as main transcript	c.397G>A	p.Ala133Thr	missense_variant	7/9
ROGDI	NR_046480.2 linkuse as main transcript	n.674G>A		non_coding_transcript_exon_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROGDI	ENST00000322048.12 linkuse as main transcript	c.667G>A	p.Ala223Thr	missense_variant	9/11	1	NM_024589.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000366

AC:

AN:

245806

Hom.:

AF XY:

0.0000301

AC XY:

AN XY:

133076

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000100

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000361

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000585

AC:

AN:

1453902

Hom.:

Cov.:

AF XY:

0.0000596

AC XY:

AN XY:

722074

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000164

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000614

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000285

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amelocerebrohypohidrotic syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2021

This sequence change replaces alanine with threonine at codon 223 of the ROGDI protein (p.Ala223Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs756917973, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with ROGDI-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

T;T;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.;.;.

MutationTaster

Benign

0.99

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.47

N;.;.;.

REVEL

Benign

0.065

Sift

Benign

0.20

T;.;.;.

Sift4G

Uncertain

0.039

D;.;.;D

Polyphen

0.53

P;.;.;.

Vest4

0.41

MutPred

0.72

Gain of glycosylation at A223 (P = 0.0699);.;.;.;

MVP

0.37

MPC

0.052

ClinPred

0.042

GERP RS

4.1

Varity_R

0.070

gMVP

0.52

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

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