8-22221700-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014759.5(PHYHIP):c.646C>G(p.Pro216Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PHYHIP NM_014759.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.61

Genes affected

PHYHIP (HGNC:16865): (phytanoyl-CoA 2-hydroxylase interacting protein) Enables protein tyrosine kinase binding activity. Involved in protein localization. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PHYHIP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHYHIP	NM_014759.5	c.646C>G	p.Pro216Ala	missense_variant	5/5	ENST00000454243.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHYHIP	ENST00000454243.7	c.646C>G	p.Pro216Ala	missense_variant	5/5	1	NM_014759.5	P1
PHYHIP	ENST00000321613.7	c.646C>G	p.Pro216Ala	missense_variant	6/6	1		P1
PHYHIP	ENST00000523252.1	c.502C>G	p.Pro168Ala	missense_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2023

The c.646C>G (p.P216A) alteration is located in exon 6 (coding exon 4) of the PHYHIP gene. This alteration results from a C to G substitution at nucleotide position 646, causing the proline (P) at amino acid position 216 to be replaced by an alanine (A). 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	0.069
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.68	P;P;.
Vest4		0.23
MutPred		0.50		Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);.;
MVP		0.42
MPC		1.4
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.35
gMVP		0.72

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: chr8-22079213;