chr8-22228319-G-T

Position:

• chr8-22228319-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014759.5(PHYHIP):​c.39C>A​(p.Asn13Lys) 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. 13/21 in silico tools predict 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: 1.02

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=0.15911475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHYHIP	NM_014759.5	c.39C>A	p.Asn13Lys	missense_variant	2/5	ENST00000454243.7	NP_055574.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHYHIP	ENST00000454243.7	c.39C>A	p.Asn13Lys	missense_variant	2/5	1	NM_014759.5	ENSP00000415491	P1
PHYHIP	ENST00000321613.7	c.39C>A	p.Asn13Lys	missense_variant	3/6	1		ENSP00000320017	P1
PHYHIP	ENST00000518274.1	n.360C>A		non_coding_transcript_exon_variant	1/3	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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.39C>A (p.N13K) alteration is located in exon 3 (coding exon 1) of the PHYHIP gene. This alteration results from a C to A substitution at nucleotide position 39, causing the asparagine (N) at amino acid position 13 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	Benign	0.25
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.087
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.66	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.040	N;N
REVEL	Benign	0.073
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.48	P;P
Vest4		0.35
MutPred		0.32		Gain of catalytic residue at N13 (P = 0.0026);Gain of catalytic residue at N13 (P = 0.0026);
MVP		0.18
MPC		1.5
ClinPred		0.77	D
GERP RS		2.3
Varity_R		0.11
gMVP		0.32

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: chr8-22085832;