NM_014759.5:c.135G>C

Variant names:

• chr8-22228223-C-G
• rs1586493730
• NM_014759.5:c.135G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014759.5(PHYHIP):​c.135G>C​(p.Glu45Asp) variant causes a missense change involving the alteration of a non-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. E45K) 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: 0.302
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23970082).

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.135G>C	p.Glu45Asp	missense	Exon 2 of 5	NP_055574.3
	PHYHIP	NM_001099335.2		c.135G>C	p.Glu45Asp	missense	Exon 3 of 6	NP_001092805.1	Q92561
	PHYHIP	NM_001363311.2		c.135G>C	p.Glu45Asp	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.135G>C	p.Glu45Asp	missense	Exon 2 of 5	ENSP00000415491.2	Q92561
	PHYHIP	ENST00000321613.7	TSL:1	c.135G>C	p.Glu45Asp	missense	Exon 3 of 6	ENSP00000320017.3	Q92561
	PHYHIP	ENST00000934692.1		c.135G>C	p.Glu45Asp	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	Uncertain	0.50
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.30
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.12
Sift	Benign	0.042	D
Sift4G	Benign	0.13	T
Polyphen		0.96	P
Vest4		0.29
MutPred		0.28		Loss of methylation at K47 (P = 0.0918)
MVP		0.19
MPC		2.2
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.20
gMVP		0.78
Mutation Taster		=78/22	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

dbSNP: rs1586493730; hg19: chr8-22085736;