rs35702995

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000187.4(HGD):c.260A>C(p.Glu87Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000729 in 1,598,508 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 6 hom. )

Consequence

HGD
NM_000187.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:3

Conservation

PhyloP100: 6.97

Publications

4 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=0.009167284).

BP6

Variant 3-120670449-T-G is Benign according to our data. Variant chr3-120670449-T-G is described in ClinVar as Benign. ClinVar VariationId is 342752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00387 (590/152304) while in subpopulation AFR AF = 0.0134 (558/41564). AF 95% confidence interval is 0.0125. There are 3 homozygotes in GnomAd4. There are 269 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

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.260A>C	p.Glu87Ala	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.260A>C	p.Glu87Ala	missense	Exon 4 of 14	ENSP00000283871.5	Q93099
HGD	ENST00000898838.1		c.260A>C	p.Glu87Ala	missense	Exon 4 of 15	ENSP00000568897.1
HGD	ENST00000898833.1		c.260A>C	p.Glu87Ala	missense	Exon 4 of 14	ENSP00000568892.1

Frequencies

GnomAD3 genomes

AF:

0.00386

AC:

588

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

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:

0.0000588

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000836

AC:

210

AN:

251280

AF XY:

0.000560

show subpopulations

Gnomad AFR exome

AF:

0.0118

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000398

AC:

575

AN:

1446204

Hom.:

Cov.:

AF XY:

0.000330

AC XY:

238

AN XY:

720550

show subpopulations

African (AFR)

AF:

0.0146

AC:

484

AN:

33092

American (AMR)

AF:

0.000537

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39644

South Asian (SAS)

AF:

0.0000465

AC:

AN:

85978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000364

AC:

AN:

1097774

Other (OTH)

AF:

0.000852

AC:

AN:

59856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00387

AC:

590

AN:

152304

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

269

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0134

AC:

558

AN:

41564

American (AMR)

AF:

0.00150

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68024

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

125

156

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:

0.00135

Hom.:

Bravo

AF:

0.00445

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alkaptonuria (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

Eigen

Benign

0.033

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0092

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.1

PhyloP100

7.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.41

Sift

Benign

0.36

Sift4G

Benign

0.46

Polyphen

0.0020

Vest4

0.67

MVP

0.90

MPC

0.10

ClinPred

0.053

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.69

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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