rs140788110

Variant names:

• chr12-121854703-C-T
• rs140788110
• NM_002150.3:c.414G>A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_002150.3(HPD):​c.414G>A​(p.Thr138Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,610,788 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (202 hom.)
• Consequence: HPD NM_002150.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9974
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.78

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 12-121854703-C-T is Benign according to our data. Variant chr12-121854703-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 307485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPD	NM_002150.3	c.414G>A	p.Thr138Thr	splice_region_variant, synonymous_variant	Exon 7 of 14	ENST00000289004.8	NP_002141.2
HPD	NM_001171993.2	c.297G>A	p.Thr99Thr	splice_region_variant, synonymous_variant	Exon 9 of 16		NP_001165464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPD	ENST00000289004.8	c.414G>A	p.Thr138Thr	splice_region_variant, synonymous_variant	Exon 7 of 14	1	NM_002150.3	ENSP00000289004.4
HPD	ENST00000543163.5	c.297G>A	p.Thr99Thr	splice_region_variant, synonymous_variant	Exon 8 of 15	5		ENSP00000441677.1
HPD	ENST00000542159.2	n.450G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 6	5

Frequencies

GnomAD3 genomes AF: 0.00506 AC: 770 AN: 152144 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0444

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0128 AC: 3207 AN: 251488 Hom.: 183 AF XY: 0.00954 AC XY: 1296 AN XY: 135916

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.0885

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00147

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00294 AC: 4282 AN: 1458526 Hom.: 202 Cov.: 30 AF XY: 0.00245 AC XY: 1775 AN XY: 725870

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.0834

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.00313

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.00264

GnomAD4 genome AF: 0.00506 AC: 771 AN: 152262 Hom.: 25 Cov.: 32 AF XY: 0.00551 AC XY: 410 AN XY: 74448

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.0444

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00308

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.000910 Hom.: 5

Bravo AF: 0.0100

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tyrosinemia type III;C2931042:Hawkinsinuria Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hawkinsinuria Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Tyrosinemia type III Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 24

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

Publications

LitVar

Other links and lift over

dbSNP: rs140788110; hg19: chr12-122292609;