rs1154510

Variant names:

• chr12-121857429-T-C
• rs1154510
• NM_002150.3:c.97A>G

Variant summary

Our verdict is Benign. The variant received -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T33T) has been classified as Likely 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:8
• Conservation: PhyloP100: 4.23
• Publications: 49 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)

TIALD (HGNC:56938):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 802899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPD	NM_002150.3	MANE Select	c.97A>G	p.Thr33Ala	missense	Exon 4 of 14	NP_002141.2	P32754-1
	HPD	NM_001171993.2		c.-21A>G		5_prime_UTR	Exon 6 of 16	NP_001165464.1	P32754-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPD	ENST00000289004.8	TSL:1 MANE Select	c.97A>G	p.Thr33Ala	missense	Exon 4 of 14	ENSP00000289004.4	P32754-1
	HPD	ENST00000868949.1		c.97A>G	p.Thr33Ala	missense	Exon 4 of 15	ENSP00000539008.1
	HPD	ENST00000868952.1		c.97A>G	p.Thr33Ala	missense	Exon 4 of 14	ENSP00000539011.1

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

GnomAD2 exomes AF: 0.845 AC: 212430 AN: 251396 AF XY: 0.848

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 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

African (AFR) AF: 0.965 AC: 32214 AN: 33370

American (AMR) AF: 0.735 AC: 32856 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 23217 AN: 26100

East Asian (EAS) AF: 0.840 AC: 33313 AN: 39664

South Asian (SAS) AF: 0.847 AC: 72914 AN: 86116

European-Finnish (FIN) AF: 0.779 AC: 41555 AN: 53372

Middle Eastern (MID) AF: 0.905 AC: 5201 AN: 5750

European-Non Finnish (NFE) AF: 0.872 AC: 964311 AN: 1105728

Other (OTH) AF: 0.875 AC: 52621 AN: 60146

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

African (AFR) AF: 0.960 AC: 39875 AN: 41536

American (AMR) AF: 0.796 AC: 12154 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 3109 AN: 3472

East Asian (EAS) AF: 0.861 AC: 4447 AN: 5166

South Asian (SAS) AF: 0.852 AC: 4110 AN: 4826

European-Finnish (FIN) AF: 0.769 AC: 8137 AN: 10576

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.869 AC: 59073 AN: 68006

Other (OTH) AF: 0.877 AC: 1855 AN: 2114

Alfa AF: 0.872 Hom.: 229693

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hawkinsinuria (2)
-	-	2	not specified (2)
-	-	2	Tyrosinemia type III;C2931042:Hawkinsinuria (2)
-	-	1	not provided (1)
-	-	1	Tyrosinemia type III (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.2
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
Mutation Taster		=238/62	polymorphism (auto)

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