6-78940868-G-A

Position:

chr6-78940868-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_017934.7(PHIP):c.5291C>T(p.Pro1764Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,616 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 Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PHIP
NM_017934.7 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 5.23

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:

IRAK1BP1 (HGNC:17368): (interleukin 1 receptor associated kinase 1 binding protein 1) Predicted to be involved in I-kappaB kinase/NF-kappaB signaling. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

IRAK1BP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PHIP. . Gene score misZ 5.1395 (greater than the threshold 3.09). Trascript score misZ 4.4358 (greater than threshold 3.09). GenCC has associacion of gene with PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, developmental delay, intellectual disability, obesity, and dysmorphic features.

BP4

Computational evidence support a benign effect (MetaRNN=0.17818889).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PHIP	NM_017934.7 linkuse as main transcript	c.5291C>T	p.Pro1764Leu	missense_variant	40/40	ENST00000275034.5	NP_060404.4
PHIP	XM_005248729.6 linkuse as main transcript	c.5288C>T	p.Pro1763Leu	missense_variant	40/40		XP_005248786.1
PHIP	XM_011535918.4 linkuse as main transcript	c.4775C>T	p.Pro1592Leu	missense_variant	37/37		XP_011534220.1
IRAK1BP1	XM_047418194.1 linkuse as main transcript	c.*37+5299G>A		intron_variant			XP_047274150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHIP	ENST00000275034.5 linkuse as main transcript	c.5291C>T	p.Pro1764Leu	missense_variant	40/40	1	NM_017934.7	ENSP00000275034	P3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151836

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151836

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74142

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PHIP-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2024

The PHIP c.5291C>T variant is predicted to result in the amino acid substitution p.Pro1764Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.0083

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.092

Sift

Uncertain

0.0060

Sift4G

Benign

0.22

Polyphen

0.36

Vest4

0.32

MVP

0.14

MPC

0.16

ClinPred

0.59

GERP RS

6.1

Varity_R

0.094

gMVP

0.083

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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