Genetic Variant PHYHIP:p.Asp293Asn (chr8-22221469-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014759.5(PHYHIP):c.877G>A(p.Asp293Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

PHYHIP
NM_014759.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.30

Variant links:

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]

PHYHIP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.16799745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHYHIP	NM_014759.5 link	c.877G>A	p.Asp293Asn	missense_variant	Exon 5 of 5	ENST00000454243.7	NP_055574.3	Q92561

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PHYHIP	ENST00000454243.7 link	c.877G>A	p.Asp293Asn	missense_variant	Exon 5 of 5	1	NM_014759.5	ENSP00000415491.2	Q92561
PHYHIP	ENST00000321613.7 link	c.877G>A	p.Asp293Asn	missense_variant	Exon 6 of 6	1		ENSP00000320017.3	Q92561
PHYHIP	ENST00000523252.1 link	c.733G>A	p.Asp245Asn	missense_variant	Exon 4 of 4	5		ENSP00000430870.1	E5RHN5

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000803

AC:

AN:

249220

Hom.:

AF XY:

0.0000961

AC XY:

AN XY:

135264

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000169

AC:

247

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

115

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000216

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000112

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000152

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000239

AC:

ESP6500EA

AF:

0.000354

AC:

ExAC

AF:

0.0000743

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.877G>A (p.D293N) alteration is located in exon 6 (coding exon 4) of the PHYHIP gene. This alteration results from a G to A substitution at nucleotide position 877, causing the aspartic acid (D) at amino acid position 293 to be replaced by an asparagine (N). 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

0.13

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.60

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.077

T;T;.

Eigen

Benign

-0.092

Eigen_PC

Benign

0.087

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.84

.;T;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.60

N;N;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.38

N;N;N

REVEL

Benign

0.093

Sift

Benign

0.35

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.038

B;B;.

Vest4

0.38

MVP

0.26

MPC

1.2

ClinPred

0.054

GERP RS

5.3

Varity_R

0.067

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over