chr6-79077904-A-G

Position:

• chr6-79077904-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3 PP5_Moderate

The ENST00000275034.5(PHIP):​c.50T>C​(p.Phe17Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,510 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. F17C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PHIP ENST00000275034.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.92

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-79077904-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1685399.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797
• PP5: Variant 6-79077904-A-G is Pathogenic according to our data. Variant chr6-79077904-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242321.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHIP	NM_017934.7	c.50T>C	p.Phe17Ser	missense_variant	2/40	ENST00000275034.5	NP_060404.4
PHIP	XM_005248729.6	c.50T>C	p.Phe17Ser	missense_variant	2/40		XP_005248786.1
PHIP	XM_011535919.2	c.50T>C	p.Phe17Ser	missense_variant	2/26		XP_011534221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHIP	ENST00000275034.5	c.50T>C	p.Phe17Ser	missense_variant	2/40	1	NM_017934.7	ENSP00000275034	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442510 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 716076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 02, 2019

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 05, 2022

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: 27900362) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.096	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.0070	B
Vest4		0.88
MutPred		0.61		Gain of disorder (P = 0.004);
MVP		0.65
MPC		3.3
ClinPred		1.0	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.86
gMVP		0.85

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

Other links and lift over

dbSNP: rs878854420; hg19: chr6-79787621;