rs1555491559

Positions:

• chr16-4801506-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024589.3(ROGDI):​c.197G>A​(p.Cys66Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000551 in 1,451,988 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ROGDI NM_024589.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.890

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.113949805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROGDI	NM_024589.3	c.197G>A	p.Cys66Tyr	missense_variant	3/11	ENST00000322048.12	NP_078865.1
ROGDI	XM_006720947.5	c.197G>A	p.Cys66Tyr	missense_variant	3/11		XP_006721010.1
ROGDI	XM_047434636.1	c.-19G>A		5_prime_UTR_variant	2/9		XP_047290592.1
ROGDI	NR_046480.2	n.259G>A		non_coding_transcript_exon_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROGDI	ENST00000322048.12	c.197G>A	p.Cys66Tyr	missense_variant	3/11	1	NM_024589.3	ENSP00000322832	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000551 AC: 8 AN: 1451988 Hom.: 0 Cov.: 31 AF XY: 0.00000555 AC XY: 4 AN XY: 721210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000722

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amelocerebrohypohidrotic syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2018

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. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ROGDI-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 66 of the ROGDI protein (p.Cys66Tyr). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Benign	0.78
DEOGEN2	Benign	0.051	T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	0.69	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.038
Sift	Benign	0.034	D;.
Sift4G	Benign	0.10	T;.
Polyphen		0.26	B;.
Vest4		0.18
MutPred		0.28		Gain of sheet (P = 0.1208);.;
MVP		0.21
MPC		0.048
ClinPred		0.17	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.38
gMVP		0.28

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: rs1555491559; hg19: chr16-4851507;