Variant 3-120628469-TGGAGGCCTTGAGTCCCCACTTTGTGACCGCCAGACTTAAAGATGATTCAAACATAAATGCCTGGAGGAAGTGACGATGGGGATGAGAAAAAAGAGGTGAGA-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_000187.4(HGD):c.1189-41_1248del(p.Ala397_Arg417del) variant causes a splice acceptor, conservative inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A397A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

HGD
NM_000187.4 splice_acceptor, conservative_inframe_deletion, splice_region, intron

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.46

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates 0.1113602391629297 fraction of the gene.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-120628469-TGGAGGCCTTGAGTCCCCACTTTGTGACCGCCAGACTTAAAGATGATTCAAACATAAATGCCTGGAGGAAGTGACGATGGGGATGAGAAAAAAGAGGTGAGA-T is Pathogenic according to our data. Variant chr3-120628469-TGGAGGCCTTGAGTCCCCACTTTGTGACCGCCAGACTTAAAGATGATTCAAACATAAATGCCTGGAGGAAGTGACGATGGGGATGAGAAAAAAGAGGTGAGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 2584691.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-120628469-TGGAGGCCTTGAGTCCCCACTTTGTGACCGCCAGACTTAAAGATGATTCAAACATAAATGCCTGGAGGAAGTGACGATGGGGATGAGAAAAAAGAGGTGAGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGD	NM_000187.4 link	c.1189-41_1248del	p.Ala397_Arg417del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 14 of 14	ENST00000283871.10	NP_000178.2	Q93099
HGD	XM_005247412.3 link	c.964-41_1023del	p.Ala322_Arg342del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 12 of 12		XP_005247469.1
HGD	XM_017006277.3 link	c.766-41_825del	p.Ala256_Arg276del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 14 of 14		XP_016861766.1	B3KW64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HGD	ENST00000283871.10 link	c.1189-41_1248del	p.Ala397_Arg417del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 14 of 14	1	NM_000187.4	ENSP00000283871.5	Q93099
HGD	ENST00000492108.5 link	n.171-41_230del		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 6	2		ENSP00000419838.1	H7C5G7
HGD	ENST00000492108.5 link	n.171-41_230del		splice_acceptor_variant, splice_region_variant, 3_prime_UTR_variant, intron_variant	Exon 6 of 6	2		ENSP00000419838.1	H7C5G7

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

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 PMID:30737480. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00204). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.