12-121856347-C-T

Variant summary

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

The NM_002150.3(HPD):​c.301G>A​(p.Glu101Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HPD
NM_002150.3 missense

Scores

8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.94
Variant links:
Genes affected
HPD (HGNC:5147): (4-hydroxyphenylpyruvate dioxygenase) The protein encoded by this gene is an enzyme in the catabolic pathway of tyrosine. The encoded protein catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate. Defects in this gene are a cause of tyrosinemia type 3 (TYRO3) and hawkinsinuria (HAWK). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

Genome browser will be placed here

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
HPDNM_002150.3 linkc.301G>A p.Glu101Lys missense_variant Exon 6 of 14 ENST00000289004.8 NP_002141.2 P32754
HPDNM_001171993.2 linkc.184G>A p.Glu62Lys missense_variant Exon 8 of 16 NP_001165464.1 P32754-2
TIALDXR_002957437.2 linkn.95C>T non_coding_transcript_exon_variant Exon 1 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HPDENST00000289004.8 linkc.301G>A p.Glu101Lys missense_variant Exon 6 of 14 1 NM_002150.3 ENSP00000289004.4 A0A0B4J1R4
HPDENST00000543163.5 linkc.184G>A p.Glu62Lys missense_variant Exon 7 of 15 5 ENSP00000441677.1 P32754-2
HPDENST00000542159.2 linkn.337G>A non_coding_transcript_exon_variant Exon 3 of 6 5
ENSG00000256811ENST00000543848.1 linkn.89C>T non_coding_transcript_exon_variant Exon 1 of 3 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461808
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727210
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Oct 29, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.301G>A (p.E101K) alteration is located in exon 6 (coding exon 6) of the HPD gene. This alteration results from a G to A substitution at nucleotide position 301, causing the glutamic acid (E) at amino acid position 101 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
0.33
BayesDel_addAF
Uncertain
0.039
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.062
T;.
Eigen
Benign
-0.11
Eigen_PC
Benign
-0.040
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.077
D
MetaRNN
Uncertain
0.72
D;D
MetaSVM
Benign
-0.48
T
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-3.4
D;D
REVEL
Uncertain
0.38
Sift
Benign
0.056
T;T
Sift4G
Benign
0.15
T;T
Vest4
0.78
MutPred
0.52
Gain of catalytic residue at I106 (P = 0.0101);.;
MVP
0.72
MPC
0.44
ClinPred
0.73
D
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs753729361; hg19: chr12-122294253; API