rs146645381
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_StrongPM2PP3PP5_Moderate
The NM_178497.5(ODAPH):c.318G>A(p.Trp106Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000064 ( 0 hom. )
Consequence
ODAPH
NM_178497.5 stop_gained
NM_178497.5 stop_gained
Scores
2
12
Clinical Significance
Conservation
PhyloP100: 0.133
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.191 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 4-75564364-G-A is Pathogenic according to our data. Variant chr4-75564364-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37219.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ODAPH | NM_178497.5 | c.318G>A | p.Trp106Ter | stop_gained | 2/2 | ENST00000311623.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ODAPH | ENST00000311623.9 | c.318G>A | p.Trp106Ter | stop_gained | 2/2 | 1 | NM_178497.5 | P1 | |
ODAPH | ENST00000511093.5 | c.*220-24G>A | intron_variant, NMD_transcript_variant | 1 | |||||
ODAPH | ENST00000435974.2 | c.362G>A | p.Gly121Asp | missense_variant | 3/3 | 2 | |||
ODAPH | ENST00000616557.1 | c.207-24G>A | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152080Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251468Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135912
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GnomAD4 exome AF: 0.0000636 AC: 93AN: 1461888Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41AN XY: 727242
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74286
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
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 | Sep 02, 2022 | The ODAPH c.318G>A variant is predicted to result in premature protein termination (p.Trp106*). This variant was reported in the compound heterozygous state within individuals with an amelogenesis imperfecta phenotype (Parry et al. 2012. PubMed ID: 22901946). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-76489574-G-A). Nonsense variants in ODAPH are expected to be pathogenic. Taken together, this variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationTaster
Benign
N;N
PROVEAN
Benign
N
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 24
Find out detailed SpliceAI scores and Pangolin per-transcript scores at