rs895959

Variant names:

• chr12-121882446-C-T
• rs895959
• NM_001171993.2:c.-447+5979G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001171993.2(HPD):​c.-447+5979G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.832 in 152,118 control chromosomes in the GnomAD database, including 52,736 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.83 (52736 hom., cov: 31)
• Consequence: HPD NM_001171993.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.224
• Publications: 6 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hawkinsinuria

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171993.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPD	NM_001171993.2		c.-447+5979G>A		intron	N/A	NP_001165464.1	P32754-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Frequencies

GnomAD3 genomes AF: 0.832 AC: 126445 AN: 152000 Hom.: 52701 Cov.: 31

Gnomad AFR AF: 0.795

Gnomad AMI AF: 0.916

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.868

Gnomad OTH AF: 0.845

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.832 AC: 126532 AN: 152118 Hom.: 52736 Cov.: 31 AF XY: 0.827 AC XY: 61509 AN XY: 74372

African (AFR) AF: 0.794 AC: 32969 AN: 41498

American (AMR) AF: 0.775 AC: 11817 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 3154 AN: 3472

East Asian (EAS) AF: 0.864 AC: 4468 AN: 5170

South Asian (SAS) AF: 0.845 AC: 4077 AN: 4826

European-Finnish (FIN) AF: 0.770 AC: 8154 AN: 10586

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.868 AC: 59003 AN: 68000

Other (OTH) AF: 0.847 AC: 1791 AN: 2114

Alfa AF: 0.859 Hom.: 28409

Bravo AF: 0.830

Asia WGS AF: 0.859 AC: 2986 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.5
DANN	Benign	0.28
PhyloP100		-0.22

Splicing

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

Other links and lift over

dbSNP: rs895959; hg19: chr12-122320352;