16-4797840-G-C

Variant names:

• chr16-4797840-G-C
• rs75818610
• NM_024589.3:c.696C>G

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.696C>G​(p.Phe232Leu) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. F232S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ROGDI NM_024589.3 missense, splice_region
• Scores: Splicing: ADA: 0.00002160
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.141
• Publications: 3 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, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROGDI	NM_024589.3	c.696C>G	p.Phe232Leu	missense_variant, splice_region_variant	Exon 10 of 11	ENST00000322048.12	NP_078865.1
ROGDI	XM_006720947.5	c.717C>G	p.Ser239Arg	missense_variant	Exon 10 of 11		XP_006721010.1
ROGDI	XM_047434636.1	c.447C>G	p.Ser149Arg	missense_variant	Exon 8 of 9		XP_047290592.1
ROGDI	NR_046480.2	n.703C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROGDI	ENST00000322048.12	c.696C>G	p.Phe232Leu	missense_variant, splice_region_variant	Exon 10 of 11	1	NM_024589.3	ENSP00000322832.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248354 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	1.3
DANN	Uncertain	0.98
DEOGEN2	Benign	0.059	T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.0	M;.;.
PhyloP100		-0.14
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.3	N;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.19	T;.;.
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		0.99	D;.;.
Vest4		0.93
MutPred		0.86		Gain of disorder (P = 0.1403);.;.;
MVP		0.23
MPC		0.056
ClinPred		0.57	D
GERP RS		-3.9
Varity_R		0.27
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.046
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: rs75818610; hg19: chr16-4847841;