rs1154510

Positions:

• chr12-121857429-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002150.3(HPD):​c.97A>G​(p.Thr33Ala) variant causes a missense change. The variant allele was found at a frequency of 0.866 in 1,607,144 control chromosomes in the GnomAD database, including 604,622 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59147 hom., cov: 32)
  • Exomes 𝑓: 0.86 (545475 hom.)
• Consequence: HPD NM_002150.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.23

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]

HPD (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.099031E-6).
• BP6: Variant 12-121857429-T-C is Benign according to our data. Variant chr12-121857429-T-C is described in ClinVar as [Benign]. Clinvar id is 802899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-121857429-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPD	NM_002150.3	c.97A>G	p.Thr33Ala	missense_variant	4/14	ENST00000289004.8	NP_002141.2
HPD	NM_001171993.2	c.-21A>G		5_prime_UTR_variant	6/16		NP_001165464.1
LOC105370035	XR_002957437.2	n.395-190T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPD	ENST00000289004.8	c.97A>G	p.Thr33Ala	missense_variant	4/14	1	NM_002150.3	ENSP00000289004.4
HPD	ENST00000543163.5	c.-21A>G		5_prime_UTR_variant	5/15	5		ENSP00000441677.1
HPD	ENST00000535114.1	n.453A>G		non_coding_transcript_exon_variant	3/4	4
HPD	ENST00000542159.2	n.155A>G		non_coding_transcript_exon_variant	1/6	5

Frequencies

GnomAD3 genomes AF: 0.880 AC: 133757 AN: 152062 Hom.: 59095 Cov.: 32

Gnomad AFR AF: 0.960

Gnomad AMI AF: 0.916

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.861

Gnomad SAS AF: 0.852

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.875

GnomAD3 exomes AF: 0.845 AC: 212430 AN: 251396 Hom.: 90406 AF XY: 0.848 AC XY: 115243 AN XY: 135878

Gnomad AFR exome AF: 0.963

Gnomad AMR exome AF: 0.728

Gnomad ASJ exome AF: 0.892

Gnomad EAS exome AF: 0.863

Gnomad SAS exome AF: 0.848

Gnomad FIN exome AF: 0.779

Gnomad NFE exome AF: 0.868

Gnomad OTH exome AF: 0.855

GnomAD4 exome AF: 0.865 AC: 1258202 AN: 1454964 Hom.: 545475 Cov.: 33 AF XY: 0.865 AC XY: 626288 AN XY: 724188

Gnomad4 AFR exome AF: 0.965

Gnomad4 AMR exome AF: 0.735

Gnomad4 ASJ exome AF: 0.890

Gnomad4 EAS exome AF: 0.840

Gnomad4 SAS exome AF: 0.847

Gnomad4 FIN exome AF: 0.779

Gnomad4 NFE exome AF: 0.872

Gnomad4 OTH exome AF: 0.875

GnomAD4 genome AF: 0.880 AC: 133865 AN: 152180 Hom.: 59147 Cov.: 32 AF XY: 0.874 AC XY: 65025 AN XY: 74394

Gnomad4 AFR AF: 0.960

Gnomad4 AMR AF: 0.796

Gnomad4 ASJ AF: 0.895

Gnomad4 EAS AF: 0.861

Gnomad4 SAS AF: 0.852

Gnomad4 FIN AF: 0.769

Gnomad4 NFE AF: 0.869

Gnomad4 OTH AF: 0.877

Alfa AF: 0.871 Hom.: 116584

Bravo AF: 0.886

TwinsUK AF: 0.879 AC: 3261

ALSPAC AF: 0.880 AC: 3391

ESP6500AA AF: 0.956 AC: 4212

ESP6500EA AF: 0.873 AC: 7505

ExAC AF: 0.850 AC: 103217

Asia WGS AF: 0.870 AC: 3024 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hawkinsinuria Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Tyrosinemia type III;C2931042:Hawkinsinuria Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 03, 2021

- -

Tyrosinemia type III Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.75
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-0.95	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	3.8	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.037
MPC		0.36
ClinPred		0.020	T
GERP RS		5.5
gMVP		0.29

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

Other links and lift over

dbSNP: rs1154510; hg19: chr12-122295335; COSMIC: COSV56641491; COSMIC: COSV56641491;