Genetic Variant ROGDI:p.Thr162Ser (chr16-4798615-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024589.3(ROGDI):c.485C>G(p.Thr162Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,423,378 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T162N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ROGDI
NM_024589.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.96

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

amelocerebrohypohidrotic syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ROGDI links:

ENSG00000285952 (HGNC:):

ENSG00000285952 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROGDI	NM_024589.3 link	c.485C>G	p.Thr162Ser	missense_variant	Exon 7 of 11	ENST00000322048.12	NP_078865.1	Q9GZN7
ROGDI	XM_006720947.5 link	c.485C>G	p.Thr162Ser	missense_variant	Exon 7 of 11		XP_006721010.1
ROGDI	XM_047434636.1 link	c.215C>G	p.Thr72Ser	missense_variant	Exon 5 of 9		XP_047290592.1
ROGDI	NR_046480.2 link	n.492C>G		non_coding_transcript_exon_variant	Exon 6 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROGDI	ENST00000322048.12 link	c.485C>G	p.Thr162Ser	missense_variant	Exon 7 of 11	1	NM_024589.3	ENSP00000322832.6		Q9GZN7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1423378

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705066

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33286

American (AMR)

AF:

0.0000261

AC:

AN:

38264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25376

East Asian (EAS)

AF:

0.00

AC:

AN:

38722

South Asian (SAS)

AF:

0.00

AC:

AN:

81390

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43838

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097520

Other (OTH)

AF:

0.00

AC:

AN:

59272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.057

T;T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.62

D;D;D

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.0

M;.;.

PhyloP100

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.6

N;.;.

REVEL

Benign

0.22

Sift

Uncertain

0.016

D;.;.

Sift4G

Benign

0.17

T;.;.

Polyphen

0.93

P;.;.

Vest4

0.77

MutPred

0.53

Gain of disorder (P = 0.0885);.;.;

MVP

0.61

MPC

0.14

ClinPred

0.96

GERP RS

4.2

Varity_R

0.34

gMVP

0.45

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over