rs2255543

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q80Q) has been classified as Uncertain significance.

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

Publications

36 publications found

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 Gene-Disease associations (from GenCC):

alkaptonuria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

HGD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 127 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.28979 (below the threshold of 3.09). Trascript score misZ: 0.53625 (below the threshold of 3.09). GenCC associations: The gene is linked to alkaptonuria.

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 VariationId is 255481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000187.4. 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
	HGD	NM_000187.4	MANE Select	c.240A>T	p.Gln80His	missense	Exon 4 of 14	NP_000178.2	Q93099

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HGD	ENST00000283871.10	TSL:1 MANE Select	c.240A>T	p.Gln80His	missense	Exon 4 of 14	ENSP00000283871.5	Q93099
HGD	ENST00000898838.1		c.240A>T	p.Gln80His	missense	Exon 4 of 15	ENSP00000568897.1
HGD	ENST00000898833.1		c.240A>T	p.Gln80His	missense	Exon 4 of 14	ENSP00000568892.1

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

GnomAD2 exomes

AF:

0.741

AC:

186129

AN:

251302

AF XY:

0.737

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 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

African (AFR)

AF:

0.765

AC:

25486

AN:

33320

American (AMR)

AF:

0.812

AC:

36307

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.770

AC:

20089

AN:

26088

East Asian (EAS)

AF:

0.601

AC:

23856

AN:

39670

South Asian (SAS)

AF:

0.702

AC:

60437

AN:

86128

European-Finnish (FIN)

AF:

0.730

AC:

38999

AN:

53414

Middle Eastern (MID)

AF:

0.764

AC:

4396

AN:

5756

European-Non Finnish (NFE)

AF:

0.743

AC:

822166

AN:

1105980

Other (OTH)

AF:

0.745

AC:

44796

AN:

60164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

13787

27574

41361

55148

68935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20060

40120

60180

80240

100300

<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:

0.751

AC:

114195

AN:

152062

Hom.:

42979

Cov.:

AF XY:

0.749

AC XY:

55650

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.764

AC:

31687

AN:

41470

American (AMR)

AF:

0.801

AC:

12236

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.779

AC:

2704

AN:

3470

East Asian (EAS)

AF:

0.631

AC:

3257

AN:

5160

South Asian (SAS)

AF:

0.701

AC:

3381

AN:

4822

European-Finnish (FIN)

AF:

0.727

AC:

7679

AN:

10566

Middle Eastern (MID)

AF:

0.759

AC:

223

AN:

294

European-Non Finnish (NFE)

AF:

0.745

AC:

50676

AN:

67986

Other (OTH)

AF:

0.778

AC:

1643

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1469

2939

4408

5878

7347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.742

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alkaptonuria (3)

not specified (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.35

(source)

DANN

Benign

0.69

DEOGEN2

Uncertain

0.58

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.043

MetaRNN

Benign

0.0000015

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.1

PhyloP100

-0.23

PrimateAI

Uncertain

0.50

PROVEAN

Benign

1.2

REVEL

Benign

0.22

Sift

Benign

0.76

Sift4G

Benign

0.20

Polyphen

0.0

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

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over