3-120628469-TGGAGGCCTTGAGTCCCCACTTTGTGACCGCCAGACTTAAAGATGATTCAAACATAAATGCCTGGAGGAAGTGACGATGGGGATGAGAAAAAAGAGGTGAGA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000187.4(HGD):c.1189-41_1248del variant causes a splice acceptor, coding sequence, 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).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HGD NM_000187.4 splice_acceptor, coding_sequence, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.46

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.

• PVS1: Splicing variant, LoF is a know mechanism of disease,
• 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/exons	MANE	UniProt
HGD	NM_000187.4	c.1189-41_1248del		splice_acceptor_variant, coding_sequence_variant, intron_variant	14/14	ENST00000283871.10
HGD	XM_005247412.3	c.964-41_1023del		splice_acceptor_variant, coding_sequence_variant, intron_variant	12/12
HGD	XM_017006277.3	c.766-41_825del		splice_acceptor_variant, coding_sequence_variant, intron_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGD	ENST00000283871.10	c.1189-41_1248del		splice_acceptor_variant, coding_sequence_variant, intron_variant	14/14	1	NM_000187.4	P1
HGD	ENST00000492108.5	c.*171-41_*230del		splice_acceptor_variant, 3_prime_UTR_variant, intron_variant, NMD_transcript_variant	6/6	2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alkaptonuria Pathogenic:1

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 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

Splicing

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: chr3-120347316;