12-121856391-AG-A

Variant names:

• chr12-121856391-AG-A
• NM_002150.3:c.256delC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002150.3(HPD):​c.256delC​(p.Leu86TrpfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HPD NM_002150.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.176

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]

TIALD (HGNC:56938):

ACMG classification

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 12-121856391-AG-A is Pathogenic according to our data. Variant chr12-121856391-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 2952980.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPD	NM_002150.3	c.256delC	p.Leu86TrpfsTer2	frameshift_variant	Exon 6 of 14	ENST00000289004.8	NP_002141.2
HPD	NM_001171993.2	c.139delC	p.Leu47TrpfsTer2	frameshift_variant	Exon 8 of 16		NP_001165464.1
TIALD	XR_002957437.2	n.141delG		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPD	ENST00000289004.8	c.256delC	p.Leu86TrpfsTer2	frameshift_variant	Exon 6 of 14	1	NM_002150.3	ENSP00000289004.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tyrosinemia type III;C2931042:Hawkinsinuria Pathogenic:1

Oct 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu86Trpfs*2) 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 is not present in population databases (gnomAD no frequency). 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-122294297;