rs374048479

Variant names:

• chr5-178211959-T-C
• rs374048479
• NM_153373.4:c.1315A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-178211959-T-C
• chr5-178211959-T-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153373.4(PHYKPL):​c.1315A>G​(p.Lys439Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: PHYKPL NM_153373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.737
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042432427).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153373.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHYKPL	NM_153373.4	MANE Select	c.1315A>G	p.Lys439Glu	missense	Exon 12 of 13	NP_699204.1	Q8IUZ5-1
	PHYKPL	NM_001278346.1		c.1192A>G	p.Lys398Glu	missense	Exon 12 of 13	NP_001265275.1	Q8IUZ5
	PHYKPL	NR_103508.1		n.1173A>G		non_coding_transcript_exon	Exon 9 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHYKPL	ENST00000308158.10	TSL:1 MANE Select	c.1315A>G	p.Lys439Glu	missense	Exon 12 of 13	ENSP00000310978.5	Q8IUZ5-1
	PHYKPL	ENST00000474052.5	TSL:1	n.*703A>G		non_coding_transcript_exon	Exon 9 of 10	ENSP00000423806.1	D6RCB8
	PHYKPL	ENST00000494126.6	TSL:1	n.1956A>G		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000107 AC: 27 AN: 251440 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1461834 Hom.: 0 Cov.: 30 AF XY: 0.000169 AC XY: 123 AN XY: 727216

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000201 AC: 224 AN: 1111968

Other (OTH) AF: 0.000116 AC: 7 AN: 60392

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.0000483 AC: 2 AN: 41414

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68024

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000124 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.81
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.74
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.22
Sift	Benign	0.56	T
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.23
MVP		0.59
MPC		0.12
ClinPred		0.0087	T
GERP RS		1.4
Varity_R		0.075
gMVP		0.55
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs374048479; hg19: chr5-177638960;