chr3-120647049-G-C

Variant names:

• chr3-120647049-G-C
• NM_000187.4:c.473C>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000187.4(HGD):​c.473C>G​(p.Pro158Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P158L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HGD NM_000187.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.10

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a strand (size 17) in uniprot entity HGD_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000187.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-120647049-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 3-120647049-G-C is Pathogenic according to our data. Variant chr3-120647049-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2626844.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-120647049-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGD	NM_000187.4	c.473C>G	p.Pro158Arg	missense_variant	Exon 8 of 14	ENST00000283871.10	NP_000178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGD	ENST00000283871.10	c.473C>G	p.Pro158Arg	missense_variant	Exon 8 of 14	1	NM_000187.4	ENSP00000283871.5
HGD	ENST00000476082.2	c.350C>G	p.Pro117Arg	missense_variant	Exon 7 of 7	5		ENSP00000419560.2
HGD	ENST00000475447.2	c.2C>G	p.Pro1Arg	missense_variant	Exon 1 of 5	3		ENSP00000417977.2
HGD	ENST00000492108.5	n.104C>G		non_coding_transcript_exon_variant	Exon 3 of 6	2		ENSP00000419838.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alkaptonuria Pathogenic:1

-

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_00047). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-8.9	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.96		Loss of catalytic residue at Q159 (P = 0.0974);.;
MVP		0.99
MPC		0.46
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-120365896;