Variant 12-121856394-T-TGATC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_002150.3(HPD):c.253_254insGATC(p.His85ArgfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HPD
NM_002150.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.51

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]

HPD links:

LOC105370035 (HGNC:):

LOC105370035 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-121856394-T-TGATC is Pathogenic according to our data. Variant chr12-121856394-T-TGATC is described in ClinVar as [Pathogenic]. Clinvar id is 2939489.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HPD	NM_002150.3 linkuse as main transcript	c.253_254insGATC	p.His85ArgfsTer8	frameshift_variant	6/14	ENST00000289004.8	NP_002141.2
LOC105370035	XR_002957437.2 linkuse as main transcript	n.144_147dup		non_coding_transcript_exon_variant	1/3
HPD	NM_001171993.2 linkuse as main transcript	c.136_137insGATC	p.His46ArgfsTer8	frameshift_variant	8/16		NP_001165464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPD	ENST00000289004.8 linkuse as main transcript	c.253_254insGATC	p.His85ArgfsTer8	frameshift_variant	6/14	1	NM_002150.3	ENSP00000289004	P1
	ENST00000543848.1 linkuse as main transcript	n.134+4_134+7dup		splice_region_variant, intron_variant, non_coding_transcript_variant		3
HPD	ENST00000543163.5 linkuse as main transcript	c.136_137insGATC	p.His46ArgfsTer8	frameshift_variant	7/15	5		ENSP00000441677		P32754-2
HPD	ENST00000542159.2 linkuse as main transcript	n.289_290insGATC		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251460

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Tyrosinemia type III;C2931042:Hawkinsinuria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 22, 2023

This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.His85Argfs*8) in the HPD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPD are known to be pathogenic (PMID: 10942115, 23036342). This variant has not been reported in the literature in individuals affected with HPD-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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