rs786204422

Variant names:

• chr3-120682101-A-G
• rs786204422
• NM_000187.4:c.11T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-120682101-A-G
• chr3-120682101-A-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HGD NM_000187.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.42
• Publications: 0 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: Pathogenic. The variant received 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• 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/Likely_pathogenic. ClinVar VariationId is 1456230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGD	NM_000187.4	c.11T>C	p.Leu4Ser	missense_variant	Exon 1 of 14	ENST00000283871.10	NP_000178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGD	ENST00000283871.10	c.11T>C	p.Leu4Ser	missense_variant	Exon 1 of 14	1	NM_000187.4	ENSP00000283871.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461734 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727190

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111880

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000164189), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alkaptonuria Pathogenic:3

-

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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). -

Mar 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with alkaptonuria (PMID: 19862842, 12501223, 16085442, Invitae). 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. For these reasons, this variant has been classified as Pathogenic. -

Oct 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HGD c.11T>C (p.Leu4Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251296 control chromosomes. c.11T>C has been reported in the literature in individuals affected with Alkaptonuria as a compound heterozygous genotype or without reported genotype (e.g. Ascher_2019, Phornphutkul_2002, Vilboux_2009). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30737480, 12501223, 19862842). ClinVar contains an entry for this variant (Variation ID: 1456230). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	0.038
Eigen_PC	Benign	0.041
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.49	P
Vest4		0.75
MutPred		0.85		Gain of catalytic residue at M1 (P = 0.0447);
MVP		0.94
MPC		0.17
ClinPred		0.93	D
GERP RS		5.1
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.24
gMVP		0.80
Mutation Taster		=80/20	polymorphism

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: rs786204422; hg19: chr3-120400948;