NM_017934.7:c.50T>C

Variant names:

• chr6-79077904-A-G
• rs878854420
• NM_017934.7:c.50T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_017934.7(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. F17L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PHIP NM_017934.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.92
• Publications: 3 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)

ENSG00000286340 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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 VariationId is 1685399.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 VariationId is 242321.Status of the report is criteria_provided_single_submitter, 1 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.50T>C	p.Phe17Ser	missense	Exon 2 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.50T>C	p.Phe17Ser	missense	Exon 2 of 40	ENSP00000275034.3	Q8WWQ0
	PHIP	ENST00000700118.1		c.50T>C	p.Phe17Ser	missense	Exon 2 of 40	ENSP00000514810.1	A0A8V8TQZ3
	PHIP	ENST00000700013.1		c.50T>C	p.Phe17Ser	missense	Exon 2 of 41	ENSP00000514754.1	A0A8V8TPK0

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

African (AFR) AF: 0.00 AC: 0 AN: 32698

American (AMR) AF: 0.00 AC: 0 AN: 43010

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25740

East Asian (EAS) AF: 0.00 AC: 0 AN: 38762

South Asian (SAS) AF: 0.00 AC: 0 AN: 83892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4850

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103664

Other (OTH) AF: 0.00 AC: 0 AN: 59488

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.9
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
PromoterAI		-0.37	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.86
gMVP		0.85
Mutation Taster		=20/80	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: rs878854420; hg19: chr6-79787621;