rs200788163
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017934.7(PHIP):c.2902C>T(p.Arg968Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000187 in 1,602,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PHIP
NM_017934.7 stop_gained
NM_017934.7 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.89
Genes affected
PHIP (HGNC:15673): (pleckstrin homology domain interacting protein) This gene encodes a protein that binds to the insulin receptor substrate 1 protein and regulates glucose transporter translocation in skeletal muscle cells. The encoded protein may also regulate growth and survival of pancreatic beta cells. Elevated copy number of this gene may be associated with melanoma severity and the encoded protein may promote melanoma metastasis in human patients. [provided by RefSeq, Oct 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-78970876-G-A is Pathogenic according to our data. Variant chr6-78970876-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PHIP | NM_017934.7 | c.2902C>T | p.Arg968Ter | stop_gained | 25/40 | ENST00000275034.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PHIP | ENST00000275034.5 | c.2902C>T | p.Arg968Ter | stop_gained | 25/40 | 1 | NM_017934.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151906Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000828 AC: 2AN: 241534Hom.: 0 AF XY: 0.0000153 AC XY: 2AN XY: 130362
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GnomAD4 exome AF: 0.00000138 AC: 2AN: 1450560Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2AN XY: 721374
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152022Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74314
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 02, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 29, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31345219, 33867250, 29209020) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 12
Find out detailed SpliceAI scores and Pangolin per-transcript scores at