12-121857417-A-G

Variant names:

• chr12-121857417-A-G
• rs1246785384
• NM_002150.3:c.109T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002150.3(HPD):​c.109T>C​(p.Cys37Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HPD NM_002150.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.46
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• tyrosinemia type III

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• hawkinsinuria

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P

TIALD (HGNC:56938):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002150.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPD	NM_002150.3	MANE Select	c.109T>C	p.Cys37Arg	missense	Exon 4 of 14	NP_002141.2
	HPD	NM_001171993.2		c.-9T>C		5_prime_UTR	Exon 6 of 16	NP_001165464.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPD	ENST00000289004.8	TSL:1 MANE Select	c.109T>C	p.Cys37Arg	missense	Exon 4 of 14	ENSP00000289004.4
	HPD	ENST00000535114.1	TSL:4	n.465T>C		non_coding_transcript_exon	Exon 3 of 4
	HPD	ENST00000542159.2	TSL:5	n.167T>C		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tyrosinemia type III;C2931042:Hawkinsinuria Uncertain:1

Nov 06, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This sequence change replaces cysteine with arginine at codon 37 of the HPD protein (p.Cys37Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HPD-related disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.63	T
PhyloP100		6.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.69
Sift	Benign	0.61	T
Sift4G	Benign	0.56	T
Vest4		0.94
MutPred		0.71		Gain of MoRF binding (P = 0.0039)
MVP		0.90
MPC		1.5
ClinPred		1.0	D
GERP RS		5.5
gMVP		0.90
Mutation Taster		=175/125	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: rs1246785384; hg19: chr12-122295323;