dbSNP rs142181517: PHYKPL:p.Glu437Val (chr5-178211964-T-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_153373.4(PHYKPL):c.1310A>T(p.Glu437Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,614,094 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0055 ( 27 hom. )

Consequence

PHYKPL
NM_153373.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 3.33

Publications

15 publications found

Variant links:

Genes affected

PHYKPL (HGNC:28249): (5-phosphohydroxy-L-lysine phospho-lyase) This is a nuclear gene encoding a mitochondrial enzyme that catalyzes the conversion of 5-phosphonooxy-L-lysine to ammonia, inorganic phosphate, and 2-aminoadipate semialdehyde. Mutations in this gene may cause phosphohydroxylysinuria. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

PHYKPL Gene-Disease associations (from GenCC):

phosphohydroxylysinuria
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

PHYKPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.088317364).

BS2

High Homozygotes in GnomAdExome4 at 27 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHYKPL	NM_153373.4 link	c.1310A>T	p.Glu437Val	missense_variant	Exon 12 of 13	ENST00000308158.10	NP_699204.1	Q8IUZ5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHYKPL	ENST00000308158.10 link	c.1310A>T	p.Glu437Val	missense_variant	Exon 12 of 13	1	NM_153373.4	ENSP00000310978.5		Q8IUZ5-1

Frequencies

GnomAD3 genomes

AF:

0.00396

AC:

603

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00659

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00354

AC:

889

AN:

251406

AF XY:

0.00355

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00277

Gnomad NFE exome

AF:

0.00616

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00551

AC:

8058

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00538

AC XY:

3911

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33480

American (AMR)

AF:

0.00235

AC:

105

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00307

AC:

164

AN:

53410

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00670

AC:

7445

AN:

1111990

Other (OTH)

AF:

0.00477

AC:

288

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

389

777

1166

1554

1943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

282

564

846

1128

1410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00396

AC:

603

AN:

152240

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

299

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41544

American (AMR)

AF:

0.00477

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00283

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00659

AC:

448

AN:

67998

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00554

Hom.:

Bravo

AF:

0.00374

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00347

AC:

421

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00611

EpiControl

AF:

0.00682

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Phosphohydroxylysinuria

Pathogenic:1Uncertain:1

Nov 30, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Nov 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.024

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.74

M_CAP

Benign

0.055

MetaRNN

Benign

0.088

MetaSVM

Benign

-0.31

MutationAssessor

Pathogenic

3.0

PhyloP100

3.3

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.85

Sift

Uncertain

0.011

Sift4G

Uncertain

0.054

Polyphen

0.17

Vest4

0.85

MVP

0.87

MPC

0.21

ClinPred

0.048

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.76

Mutation Taster

=81/19

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over