rs2255543

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000187.4(HGD):c.240A>T(p.Gln80His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.741 in 1,607,270 control chromosomes in the GnomAD database, including 442,525 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 42979 hom., cov: 32)

Exomes 𝑓: 0.74 ( 399546 hom. )

Consequence

HGD
NM_000187.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.227

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5010601E-6).

BP6

Variant 3-120670469-T-A is Benign according to our data. Variant chr3-120670469-T-A is described in ClinVar as [Benign]. Clinvar id is 255481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-120670469-T-A is described in Lovd as [Benign]. Variant chr3-120670469-T-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGD	NM_000187.4 link	c.240A>T	p.Gln80His	missense_variant	Exon 4 of 14	ENST00000283871.10	NP_000178.2	Q93099

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGD	ENST00000283871.10 link	c.240A>T	p.Gln80His	missense_variant	Exon 4 of 14	1	NM_000187.4	ENSP00000283871.5		Q93099

Frequencies

GnomAD3 genomes

AF:

0.751

AC:

114080

AN:

151944

Hom.:

42926

Cov.:

show subpopulations

Gnomad AFR

AF:

0.764

Gnomad AMI

AF:

0.779

Gnomad AMR

AF:

0.801

Gnomad ASJ

AF:

0.779

Gnomad EAS

AF:

0.631

Gnomad SAS

AF:

0.701

Gnomad FIN

AF:

0.727

Gnomad MID

AF:

0.753

Gnomad NFE

AF:

0.745

Gnomad OTH

AF:

0.778

GnomAD3 exomes

AF:

0.741

AC:

186129

AN:

251302

Hom.:

69378

AF XY:

0.737

AC XY:

100043

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.761

Gnomad AMR exome

AF:

0.814

Gnomad ASJ exome

AF:

0.774

Gnomad EAS exome

AF:

0.655

Gnomad SAS exome

AF:

0.695

Gnomad FIN exome

AF:

0.725

Gnomad NFE exome

AF:

0.741

Gnomad OTH exome

AF:

0.752

GnomAD4 exome

AF:

0.740

AC:

1076532

AN:

1455208

Hom.:

399546

Cov.:

AF XY:

0.738

AC XY:

534834

AN XY:

724356

show subpopulations

Gnomad4 AFR exome

AF:

0.765

Gnomad4 AMR exome

AF:

0.812

Gnomad4 ASJ exome

AF:

0.770

Gnomad4 EAS exome

AF:

0.601

Gnomad4 SAS exome

AF:

0.702

Gnomad4 FIN exome

AF:

0.730

Gnomad4 NFE exome

AF:

0.743

Gnomad4 OTH exome

AF:

0.745

GnomAD4 genome

AF:

0.751

AC:

114195

AN:

152062

Hom.:

42979

Cov.:

AF XY:

0.749

AC XY:

55650

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.764

Gnomad4 AMR

AF:

0.801

Gnomad4 ASJ

AF:

0.779

Gnomad4 EAS

AF:

0.631

Gnomad4 SAS

AF:

0.701

Gnomad4 FIN

AF:

0.727

Gnomad4 NFE

AF:

0.745

Gnomad4 OTH

AF:

0.778

Alfa

AF:

0.742

Hom.:

31639

Bravo

AF:

0.758

TwinsUK

AF:

0.734

AC:

2722

ALSPAC

AF:

0.731

AC:

2816

ESP6500AA

AF:

0.757

AC:

3335

ESP6500EA

AF:

0.736

AC:

6328

ExAC

AF:

0.735

AC:

89243

Asia WGS

AF:

0.670

AC:

2330

AN:

3476

EpiCase

AF:

0.745

EpiControl

AF:

0.747

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Alkaptonuria

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.35

DANN

Benign

0.69

DEOGEN2

Uncertain

0.58

D;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.043

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.1

N;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

1.2

N;N

REVEL

Benign

0.22

Sift

Benign

0.76

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0

B;.

Vest4

0.064

MutPred

0.31

Gain of catalytic residue at Q80 (P = 0.1333);.;

MPC

0.084

ClinPred

0.00086

GERP RS

-2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over