Genetic Variant HPD:c.324+20G>A (chr12-121856304-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_002150.3(HPD):c.324+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,604,710 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 2 hom. )

Consequence

HPD
NM_002150.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.265

Publications

0 publications found

Variant links:

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)

HPD links:

TIALD (HGNC:56938):

TIALD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 12-121856304-C-T is Benign according to our data. Variant chr12-121856304-C-T is described in ClinVar as Benign. ClinVar VariationId is 1166574.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00202 (308/152310) while in subpopulation AFR AF = 0.00669 (278/41578). AF 95% confidence interval is 0.00604. There are 0 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,Unknown,AD gene

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.324+20G>A		intron	N/A	NP_002141.2	P32754-1
	HPD	NM_001171993.2		c.207+20G>A		intron	N/A	NP_001165464.1	P32754-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HPD	ENST00000289004.8	TSL:1 MANE Select	c.324+20G>A	intron	N/A	ENSP00000289004.4	P32754-1
HPD	ENST00000868949.1		c.324+20G>A	intron	N/A	ENSP00000539008.1
HPD	ENST00000868952.1		c.324+20G>A	intron	N/A	ENSP00000539011.1

Frequencies

GnomAD3 genomes

AF:

0.00201

AC:

306

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00666

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000620

AC:

156

AN:

251426

AF XY:

0.000412

show subpopulations

Gnomad AFR exome

AF:

0.00757

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000196

AC:

284

AN:

1452400

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

112

AN XY:

723194

show subpopulations

African (AFR)

AF:

0.00654

AC:

218

AN:

33312

American (AMR)

AF:

0.000649

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000813

AC:

AN:

86054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103356

Other (OTH)

AF:

0.000483

AC:

AN:

60096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00202

AC:

308

AN:

152310

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00669

AC:

278

AN:

41578

American (AMR)

AF:

0.00183

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.00255

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Tyrosinemia type III;C2931042:Hawkinsinuria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.6

(source)

DANN

Benign

0.69

PhyloP100

-0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over