rs569846003

chr3-120650861-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000187.4(HGD):c.347T>C(p.Leu116Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: HGD NM_000187.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 8.68

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_000187.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 3-120650861-A-G is Pathogenic according to our data. Variant chr3-120650861-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554869.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr3-120650861-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGD	NM_000187.4	c.347T>C	p.Leu116Pro	missense_variant	6/14	ENST00000283871.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGD	ENST00000283871.10	c.347T>C	p.Leu116Pro	missense_variant	6/14	1	NM_000187.4	P1
HGD	ENST00000476082.2	c.224T>C	p.Leu75Pro	missense_variant	5/7	5
HGD	ENST00000485313.5	n.455T>C		non_coding_transcript_exon_variant	7/7	5
HGD	ENST00000492108.5			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251348 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1460656 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 726704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alkaptonuria Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 116 of the HGD protein (p.Leu116Pro). This variant is present in population databases (rs569846003, gnomAD 0.04%). This missense change has been observed in individual(s) with alkaptonuria (PMID: 23430897, 25681086, 32212000). ClinVar contains an entry for this variant (Variation ID: 554869). 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 expected to disrupt HGD protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2017	- -
Pathogenic, no assertion criteria provided	research	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	-	The variant was described in AKU patient in PMID:23430897. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00026). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jun 24, 2023	The heterozygous variant c.347T>C (p.Leu116Pro) has been identified in compound heterozygous state with c.518T>C (p.Leu173Pro) in a proband with alkaptonuria. This variant is present in exon 6 is in a mutational hotspot region where 10 pathogenic variants have been reported so far (PM1_moderate). In this gene, 79 pathogenic missense variants (PP2_supporting) have been reported. Variant has been found 0.0044% in gnomAD (aggregated) (PM2_Moderate). This variant has been previously reported: PMID:25681086 (PP5_strong). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		1.0
MutPred		0.88		Loss of stability (P = 0.0289);.;
MVP		0.99
MPC		0.61
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs569846003; hg19: chr3-120369708;