rs1554212744

Variant names:

• chr6-79060708-TAA-T
• rs1554212744
• NM_017934.7:c.298_299delTT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_017934.7(PHIP):​c.298_299delTT​(p.Leu100IlefsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHIP NM_017934.7 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.72
• Publications: 0 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, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000298699 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-79060708-TAA-T is Pathogenic according to our data. Variant chr6-79060708-TAA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 545395.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017934.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHIP	NM_017934.7	MANE Select	c.298_299delTT	p.Leu100IlefsTer13	frameshift	Exon 5 of 40	NP_060404.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHIP	ENST00000275034.5	TSL:1 MANE Select	c.298_299delTT	p.Leu100IlefsTer13	frameshift	Exon 5 of 40	ENSP00000275034.3	Q8WWQ0
	PHIP	ENST00000700118.1		c.298_299delTT	p.Leu100IlefsTer13	frameshift	Exon 5 of 40	ENSP00000514810.1	A0A8V8TQZ3
	PHIP	ENST00000700013.1		c.298_299delTT	p.Leu100IlefsTer13	frameshift	Exon 5 of 41	ENSP00000514754.1	A0A8V8TPK0

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554212744; hg19: chr6-79770425;