NM_024589.3:c.393C>G

Variant names:

• chr16-4799725-G-C
• rs143095485
• NM_024589.3:c.393C>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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. D131H) 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:5
• Conservation: PhyloP100: -0.609
• Publications: 2 publications found

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: PanelApp Australia, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000285952 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 261742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024589.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROGDI	NM_024589.3	MANE Select	c.393C>G	p.Asp131Glu	missense	Exon 6 of 11	NP_078865.1	Q9GZN7
	ROGDI	NR_046480.2		n.400C>G		non_coding_transcript_exon	Exon 5 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROGDI	ENST00000322048.12	TSL:1 MANE Select	c.393C>G	p.Asp131Glu	missense	Exon 6 of 11	ENSP00000322832.6	Q9GZN7
	ROGDI	ENST00000907806.1		c.393C>G	p.Asp131Glu	missense	Exon 6 of 11	ENSP00000577865.1
	ROGDI	ENST00000912071.1		c.393C>G	p.Asp131Glu	missense	Exon 6 of 11	ENSP00000582130.1

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

GnomAD2 exomes AF: 0.00464 AC: 1163 AN: 250636 AF XY: 0.00339

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 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

African (AFR) AF: 0.0631 AC: 2112 AN: 33456

American (AMR) AF: 0.00342 AC: 153 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5764

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111792

Other (OTH) AF: 0.00333 AC: 201 AN: 60372

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

African (AFR) AF: 0.0614 AC: 2548 AN: 41518

American (AMR) AF: 0.00706 AC: 108 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.0133 AC: 28 AN: 2108

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Amelocerebrohypohidrotic syndrome (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.61
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.080
Sift	Benign	0.31	T
Sift4G	Benign	0.56	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
Mutation Taster		=86/14	polymorphism (auto)

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

Other links and lift over

dbSNP: rs143095485; hg19: chr16-4849726;