chr8-22228225-C-T

Variant names:

• chr8-22228225-C-T
• NM_014759.5:c.133G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014759.5(PHYHIP):​c.133G>A​(p.Glu45Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E45D) has been classified 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: 7.89
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30919123).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014759.5. 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
	PHYHIP	NM_014759.5	MANE Select	c.133G>A	p.Glu45Lys	missense	Exon 2 of 5	NP_055574.3
	PHYHIP	NM_001099335.2		c.133G>A	p.Glu45Lys	missense	Exon 3 of 6	NP_001092805.1	Q92561
	PHYHIP	NM_001363311.2		c.133G>A	p.Glu45Lys	missense	Exon 3 of 7	NP_001350240.1	Q92561

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHYHIP	ENST00000454243.7	TSL:1 MANE Select	c.133G>A	p.Glu45Lys	missense	Exon 2 of 5	ENSP00000415491.2	Q92561
	PHYHIP	ENST00000321613.7	TSL:1	c.133G>A	p.Glu45Lys	missense	Exon 3 of 6	ENSP00000320017.3	Q92561
	PHYHIP	ENST00000934692.1		c.133G>A	p.Glu45Lys	missense	Exon 3 of 6	ENSP00000604751.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.091	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Benign	0.71	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Benign	0.15	T
Sift4G	Uncertain	0.060	T
Polyphen		0.92	P
Vest4		0.45
MutPred		0.35		Gain of MoRF binding (P = 0.0056)
MVP		0.16
MPC		2.5
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.24
gMVP		0.91
Mutation Taster		=60/40	polymorphism

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

hg19: chr8-22085738;