NM_017934.7:c.5241T>G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_017934.7(PHIP):c.5241T>G(p.Asp1747Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PHIP
NM_017934.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.08564535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHIP	NM_017934.7 link	c.5241T>G	p.Asp1747Glu	missense_variant	Exon 40 of 40	ENST00000275034.5	NP_060404.4	Q8WWQ0
PHIP	XM_005248729.6 link	c.5238T>G	p.Asp1746Glu	missense_variant	Exon 40 of 40		XP_005248786.1	A0A8V8TPV5
PHIP	XM_011535918.4 link	c.4725T>G	p.Asp1575Glu	missense_variant	Exon 37 of 37		XP_011534220.1
IRAK1BP1	XM_047418194.1 link	c.*37+5349A>C		intron_variant	Intron 3 of 3		XP_047274150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHIP	ENST00000275034.5 link	c.5241T>G	p.Asp1747Glu	missense_variant	Exon 40 of 40	1	NM_017934.7	ENSP00000275034.3		Q8WWQ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727144

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5241T>G (p.D1747E) alteration is located in exon 40 (coding exon 40) of the PHIP gene. This alteration results from a T to G substitution at nucleotide position 5241, causing the aspartic acid (D) at amino acid position 1747 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.038

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.61

M_CAP

Benign

0.0068

MetaRNN

Benign

0.086

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.26

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.38

REVEL

Benign

0.042

Sift

Benign

0.20

Sift4G

Benign

1.0

Polyphen

0.26

Vest4

0.081

MutPred

0.17

Gain of solvent accessibility (P = 0.0155);

MVP

0.22

MPC

0.15

ClinPred

0.14

GERP RS

3.7

Varity_R

0.059

gMVP

0.093

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over