chr6-78940904-T-A

Position:

• chr6-78940904-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_017934.7(PHIP):​c.5255A>T​(p.Glu1752Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PHIP NM_017934.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.56

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.17495406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHIP	NM_017934.7	c.5255A>T	p.Glu1752Val	missense_variant	40/40	ENST00000275034.5	NP_060404.4
PHIP	XM_005248729.6	c.5252A>T	p.Glu1751Val	missense_variant	40/40		XP_005248786.1
PHIP	XM_011535918.4	c.4739A>T	p.Glu1580Val	missense_variant	37/37		XP_011534220.1
IRAK1BP1	XM_047418194.1	c.*37+5335T>A		intron_variant			XP_047274150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHIP	ENST00000275034.5	c.5255A>T	p.Glu1752Val	missense_variant	40/40	1	NM_017934.7	ENSP00000275034	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.085	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.11
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.20	T
Polyphen		0.79	P
Vest4		0.32
MutPred		0.23		Gain of helix (P = 0.0496);
MVP		0.18
MPC		0.21
ClinPred		0.45	T
GERP RS		6.1
Varity_R		0.10
gMVP		0.21

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.

Other links and lift over

hg19: chr6-79650621;