chr16-4797955-A-T

Variant names:

• chr16-4797955-A-T
• rs549672547
• NM_024589.3:c.678T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024589.3(ROGDI):​c.678T>A​(p.His226Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. H226R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ROGDI NM_024589.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36
• Publications: 0 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000285952 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROGDI	NM_024589.3	c.678T>A	p.His226Gln	missense_variant	Exon 9 of 11	ENST00000322048.12	NP_078865.1
ROGDI	XM_006720947.5	c.678T>A	p.His226Gln	missense_variant	Exon 9 of 11		XP_006721010.1
ROGDI	XM_047434636.1	c.408T>A	p.His136Gln	missense_variant	Exon 7 of 9		XP_047290592.1
ROGDI	NR_046480.2	n.685T>A		non_coding_transcript_exon_variant	Exon 8 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROGDI	ENST00000322048.12	c.678T>A	p.His226Gln	missense_variant	Exon 9 of 11	1	NM_024589.3	ENSP00000322832.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.062	T;T;T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.0	M;.;.;.
PhyloP100		2.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N;.;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.0080	D;.;.;.
Sift4G	Uncertain	0.011	D;.;.;D
Polyphen		1.0	D;.;.;.
Vest4		0.76
MutPred		0.86		Gain of catalytic residue at M231 (P = 0.029);.;.;.;
MVP		0.25
MPC		0.17
ClinPred		0.81	D
GERP RS		4.2
Varity_R		0.36
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs549672547; hg19: chr16-4847956;