Genetic Variant HPD:p.Val340Met (chr12-121839985-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002150.3(HPD):c.1018G>A(p.Val340Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V340L) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HPD
NM_002150.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13

Publications

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

HPD links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15674937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPD	NM_002150.3 link	c.1018G>A	p.Val340Met	missense_variant	Exon 13 of 14	ENST00000289004.8	NP_002141.2	P32754
HPD	NM_001171993.2 link	c.901G>A	p.Val301Met	missense_variant	Exon 15 of 16		NP_001165464.1	P32754-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPD	ENST00000289004.8 link	c.1018G>A	p.Val340Met	missense_variant	Exon 13 of 14	1	NM_002150.3	ENSP00000289004.4		A0A0B4J1R4
HPD	ENST00000543163.5 link	c.901G>A	p.Val301Met	missense_variant	Exon 14 of 15	5		ENSP00000441677.1		P32754-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.014

T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.1

PhyloP100

1.1

PrimateAI

Benign

0.31

PROVEAN

Benign

0.33

N;N

REVEL

Benign

0.028

Sift

Benign

0.30

T;T

Sift4G

Benign

0.32

T;T

Vest4

0.15

MutPred

0.38

Gain of catalytic residue at K338 (P = 0.0012);.;

MVP

0.58

MPC

0.38

ClinPred

0.46

GERP RS

-0.54

gMVP

0.63

Mutation Taster

=86/14

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over