Genetic Variant PHYHIPL:p.Arg299Cys (chr10-59245355-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_032439.4(PHYHIPL):c.895C>T(p.Arg299Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PHYHIPL
NM_032439.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.92

Variant links:

Genes affected

PHYHIPL (HGNC:29378): (phytanoyl-CoA 2-hydroxylase interacting protein like) Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PHYHIPL links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHYHIPL	NM_032439.4 link	c.895C>T	p.Arg299Cys	missense_variant	Exon 5 of 5	ENST00000373880.9	NP_115815.2	Q96FC7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PHYHIPL	ENST00000373880.9 link	c.895C>T	p.Arg299Cys	missense_variant	Exon 5 of 5	1	NM_032439.4	ENSP00000362987.4	Q96FC7-1
PHYHIPL	ENST00000373878.3 link	c.817C>T	p.Arg273Cys	missense_variant	Exon 5 of 5	1		ENSP00000362985.3	Q96FC7-2
PHYHIPL	ENST00000486074.2 link	n.*836C>T		non_coding_transcript_exon_variant	Exon 6 of 6	2		ENSP00000423634.1	Q96FC7-3
PHYHIPL	ENST00000486074.2 link	n.*836C>T		3_prime_UTR_variant	Exon 6 of 6	2		ENSP00000423634.1	Q96FC7-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.895C>T (p.R299C) alteration is located in exon 5 (coding exon 5) of the PHYHIPL gene. This alteration results from a C to T substitution at nucleotide position 895, causing the arginine (R) at amino acid position 299 to be replaced by a cysteine (C). 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

0.26

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.039

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.82

MutPred

0.50

Gain of catalytic residue at L300 (P = 0.0318);.;

MVP

0.49

MPC

1.5

ClinPred

0.99

GERP RS

5.7

Varity_R

0.57

gMVP

0.37

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