4-75556133-GGTAAC-ATGCTGGTTACTGGTA

Position:

• chr4-75556133-GGTAAC-ATGCTGGTTACTGGTA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_178497.5(ODAPH):​c.51_56delGGTAACinsATGCTGGTTACTGGTA​(p.Val18fs) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ODAPH NM_178497.5 frameshift, missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.799

Genes affected

ODAPH (HGNC:26300): (odontogenesis associated phosphoprotein) Dental enamel forms the outer cap of teeth and is the hardest substance found in vertebrates. This gene is thought to encode an extracellular matrix acidic phosphoprotein that has a function in enamel mineralization during amelogenesis. Mutations in this gene are associated with recessive hypomineralized amelogenesis imperfecta. [provided by RefSeq, Oct 2012]

ODAPH (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.87 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-75556133-GGTAAC-ATGCTGGTTACTGGTA is Pathogenic according to our data. Variant chr4-75556133-GGTAAC-ATGCTGGTTACTGGTA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37220.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ODAPH	NM_178497.5	c.51_56delGGTAACinsATGCTGGTTACTGGTA	p.Val18fs	frameshift_variant, missense_variant	1/2	ENST00000311623.9	NP_848592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAPH	ENST00000311623.9	c.51_56delGGTAACinsATGCTGGTTACTGGTA	p.Val18fs	frameshift_variant, missense_variant	1/2	1	NM_178497.5	ENSP00000311307.5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Amelogenesis imperfecta hypomaturation type 2A4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 07, 2012

- -

ODAPH-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2023

The ODAPH c.51_56delinsATGCTGGTTACTGGTA variant is predicted to result in a frameshift and premature protein termination (p.Val18Cysfs*23). This variant has been reported in both the homozygous and compound heterozygous states in individuals with amelogenesis imperfecta (Parry et al 2012. PubMed ID: 22901946). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in ODAPH are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1560558455; hg19: chr4-76481343;