8-22228223-C-G

Variant names:

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

Variant summary

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

• 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

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 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHYHIP	NM_014759.5	c.135G>C	p.Glu45Asp	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.135G>C	p.Glu45Asp	missense_variant	Exon 2 of 5	1	NM_014759.5	ENSP00000415491.2
PHYHIP	ENST00000321613.7	c.135G>C	p.Glu45Asp	missense_variant	Exon 3 of 6	1		ENSP00000320017.3
PHYHIP	ENST00000518274.1	n.456G>C		non_coding_transcript_exon_variant	Exon 1 of 3	2
PHYHIP	ENST00000522869.5	n.31G>C		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

Aug 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.135G>C (p.E45D) alteration is located in exon 3 (coding exon 1) of the PHYHIP gene. This alteration results from a G to C substitution at nucleotide position 135, causing the glutamic acid (E) at amino acid position 45 to be replaced by an aspartic acid (D). 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	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;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;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.12
Sift	Benign	0.042	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.96	P;P
Vest4		0.29
MutPred		0.28		Loss of methylation at K47 (P = 0.0918);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

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: chr8-22085736;