rs768324201

Variant names:

• chr6-79060680-G-A
• rs768324201
• NM_017934.7:c.328C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-79060680-G-A
• chr6-79060680-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R110S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PHIP NM_017934.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.36
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• developmental delay, intellectual disability, obesity, and dysmorphic features

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000298699 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-79060679-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1301421.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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	c.328C>T	p.Arg110Cys	missense_variant	Exon 5 of 40	ENST00000275034.5	NP_060404.4

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459452 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726042

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 85864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110864

Other (OTH) AF: 0.00 AC: 0 AN: 60270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.001814), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

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) -

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

- -

PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome Pathogenic:2

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 -

Jan 23, 2025

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Mar 20, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.58		Loss of MoRF binding (P = 0.003);
MVP		0.82
MPC		2.9
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.81
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs768324201; hg19: chr6-79770397; COSMIC: COSV51504515;