rs2255543

Variant names:

• chr3-120670469-T-A
• rs2255543
• NM_000187.4:c.240A>T

Your query was ambiguous. Multiple possible variants found:

• chr3-120670469-T-A
• chr3-120670469-T-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42979 hom., cov: 32)
  • Exomes 𝑓: 0.74 (399546 hom.)
• Consequence: HGD NM_000187.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.227
• Publications: 36 publications found

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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

Selected	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

Ensembl Transcripts

Selected	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
	HGD	ENST00000476082.2	TSL:5	c.117A>T	p.Gln39His	missense	Exon 3 of 7	ENSP00000419560.2
	HGD	ENST00000466528.5	TSL:2	n.266A>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.751 AC: 114080 AN: 151944 Hom.: 42926 Cov.: 32

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

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.: 34 AF XY: 0.738 AC XY: 534834 AN XY: 724356

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

GnomAD4 genome AF: 0.751 AC: 114195 AN: 152062 Hom.: 42979 Cov.: 32 AF XY: 0.749 AC XY: 55650 AN XY: 74330

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

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

Submissions by phenotype

not specified Benign:3

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Alkaptonuria Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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.

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.35
DANN	Benign	0.69
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.043	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.23
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.22
Sift	Benign	0.76	T
Sift4G	Benign	0.20	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	T
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)

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

Other links and lift over

dbSNP: rs2255543; hg19: chr3-120389316; COSMIC: COSV52199452; COSMIC: COSV52199452;