16-4802386-A-G

Variant names:

• chr16-4802386-A-G
• rs1555491894
• NM_024589.3:c.113T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024589.3(ROGDI):​c.113T>C​(p.Leu38Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000705 in 1,418,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L38R) 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.89
• 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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROGDI	NM_024589.3	c.113T>C	p.Leu38Pro	missense_variant	Exon 2 of 11	ENST00000322048.12	NP_078865.1
ROGDI	XM_006720947.5	c.113T>C	p.Leu38Pro	missense_variant	Exon 2 of 11		XP_006721010.1
ROGDI	NR_046480.2	n.175T>C		non_coding_transcript_exon_variant	Exon 2 of 10
ROGDI	XM_047434636.1	c.-103T>C		5_prime_UTR_variant	Exon 1 of 9		XP_047290592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROGDI	ENST00000322048.12	c.113T>C	p.Leu38Pro	missense_variant	Exon 2 of 11	1	NM_024589.3	ENSP00000322832.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418598 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 703980

African (AFR) AF: 0.00 AC: 0 AN: 31762

American (AMR) AF: 0.00 AC: 0 AN: 38158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24618

East Asian (EAS) AF: 0.00 AC: 0 AN: 37462

South Asian (SAS) AF: 0.00 AC: 0 AN: 80830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1094534

Other (OTH) AF: 0.00 AC: 0 AN: 58532

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	-0.022	T
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		6.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.3	D;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.93		Loss of stability (P = 0.008);Loss of stability (P = 0.008);
MVP		0.47
MPC		0.21
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		-0.19	Neutral
Varity_R		0.98
gMVP		0.88

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: rs1555491894; hg19: chr16-4852387;