8-22228225-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• 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

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 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHYHIP	NM_014759.5	c.133G>A	p.Glu45Lys	missense_variant	Exon 2 of 5	ENST00000454243.7	NP_055574.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHYHIP	ENST00000454243.7	c.133G>A	p.Glu45Lys	missense_variant	Exon 2 of 5	1	NM_014759.5	ENSP00000415491.2
PHYHIP	ENST00000321613.7	c.133G>A	p.Glu45Lys	missense_variant	Exon 3 of 6	1		ENSP00000320017.3
PHYHIP	ENST00000518274.1	n.454G>A		non_coding_transcript_exon_variant	Exon 1 of 3	2
PHYHIP	ENST00000522869.5	n.29G>A		non_coding_transcript_exon_variant	Exon 1 of 3	2

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

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.133G>A (p.E45K) alteration is located in exon 3 (coding exon 1) of the PHYHIP gene. This alteration results from a G to A substitution at nucleotide position 133, causing the glutamic acid (E) at amino acid position 45 to be replaced by a lysine (K). 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	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;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;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.11
Sift	Benign	0.15	T;T
Sift4G	Uncertain	0.060	T;T
Polyphen		0.92	P;P
Vest4		0.45
MutPred		0.35		Gain of MoRF binding (P = 0.0056);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

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: chr8-22085738;