Variant chr3-120682101-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_000187.4(HGD):c.11T>C(p.Leu4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

HGD
NM_000187.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 2.42

Variant links:

Genes affected

HGD (HGNC:4892): (homogentisate 1,2-dioxygenase) This gene encodes the enzyme homogentisate 1,2 dioxygenase. This enzyme is involved in the catabolism of the amino acids tyrosine and phenylalanine. Mutations in this gene are the cause of the autosomal recessive metabolism disorder alkaptonuria.[provided by RefSeq, May 2010]

HGD links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

PP5

Variant 3-120682101-A-G is Pathogenic according to our data. Variant chr3-120682101-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1456230.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-120682101-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGD	NM_000187.4 linkuse as main transcript	c.11T>C	p.Leu4Ser	missense_variant	1/14	ENST00000283871.10	NP_000178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGD	ENST00000283871.10 linkuse as main transcript	c.11T>C	p.Leu4Ser	missense_variant	1/14	1	NM_000187.4	ENSP00000283871	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461734

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Alkaptonuria

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	-	The variant was originally described in AKU patient in PMID:12501223. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00002). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 31, 2021	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HGD protein function. This variant has been observed in individual(s) with alkaptonuria (PMID: 19862842, 12501223, 16085442, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with serine at codon 4 of the HGD protein (p.Leu4Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Benign

0.038

Eigen_PC

Benign

0.041

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.0070

Polyphen

0.49

Vest4

0.75

MutPred

0.85

Gain of catalytic residue at M1 (P = 0.0447);

MVP

0.94

MPC

0.17

ClinPred

0.93

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.24

gMVP

0.80

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over