rs768324201

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_017934.7(PHIP):c.328C>T(p.Arg110Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,452 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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PHIP
NM_017934.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.36

Variant links:

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]

PHIP links:

LOC124901346 (HGNC:):

LOC124901346 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the PHIP gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 29 curated benign missense variants. Gene score misZ: 5.1395 (above the threshold of 3.09). Trascript score misZ: 4.4358 (above the threshold of 3.09). GenCC associations: The gene is linked to PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, developmental delay, intellectual disability, obesity, and dysmorphic features.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

PP5

Variant 6-79060680-G-A is Pathogenic according to our data. Variant chr6-79060680-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 975951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHIP	NM_017934.7 link	c.328C>T	p.Arg110Cys	missense_variant	Exon 5 of 40	ENST00000275034.5	NP_060404.4	Q8WWQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHIP	ENST00000275034.5 link	c.328C>T	p.Arg110Cys	missense_variant	Exon 5 of 40	1	NM_017934.7	ENSP00000275034.3		Q8WWQ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459452

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Aug 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 110 of the PHIP protein (p.Arg110Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PHIP-related conditions (PMID: 29209020). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 975951). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PHIP protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jan 21, 2019

Molecular Genetics laboratory, Necker Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29209020, 28263302, 27479843) -

Inborn genetic diseases

Pathogenic:1

Mar 20, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome

Pathogenic:1

Oct 01, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2_MOD,PS4_MOD,PM5,PM2_SUP,PP2 -

Intellectual disability

Pathogenic:1

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PHIP-related disorder

Pathogenic:1

Aug 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PHIP c.328C>T variant is predicted to result in the amino acid substitution p.Arg110Cys. This variant has been reported as a de novo variant in at least one patient with intellectual disability, developmental delays, behavioral problems, and dysmorphic facial features (Individual 10, Supplemental note, Jansen et al. 2018. PubMed ID: 29209020; Table S2, Lelieveld et al. 2016. PubMed ID: 27479843), and was also reported as de novo in a patient with autism spectrum disorder (Table S3, Yuen et al. 2017. PubMed ID: 28263302). At PreventionGenetics, we have also observed this variant to occur de novo in a patient with clinical features consistent with a PHIP-related disorder (internal data). Additionally, a different de novo variant affecting the same amino acid (p.Arg110Ser) has been reported in an individual with similar features (Individual 5, Supplemental note, Jansen et al. 2018. PubMed ID: 29209020). We interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.6

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.8

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.82

MutPred

0.58

Loss of MoRF binding (P = 0.003);

MVP

0.82

MPC

2.9

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over