rs1553721650

Positions:

• chr3-120675486-AATGCTCACATCCATGGTGTTCAAGGGGAATATGAGGGATTCTCTTTAACTCTGGATTTTTGGGGATCCTACTGGAAACCCTACAGTTAATTTCACTAGTTTGGATTGGCTGCTGTGCCACCAATCCAATTTTAATCTTTGTGTTGTCATTGCTCTGTATCTTCATTGCCCCTATGACTTGGGAAACCTCTAGACAGTTCACAGGCTAGATTGGAAGAGCCACGGTGGGTGGAGGCACTTTGGCCTGAAAGCTAGTCATCCAGGAATAGGATTCAGAGCTCTTCTAAGCACTTTATTTGCTCATACCTGTCCTTCTGGCAGGGAACCTGGGCAGCGAGGATCCTCTGAAGAACACTCATTCCCAAATCCAGAAATGTACTGTAGGTGACAAAGACACAAATGCCACCATTAGCAGGATTTAAAGAGCATTTCAGAAAATTGGCAGTTTACTAAGGTAAGAATTTCTATATGGACCTATGTTTGTGTATGATGTTCCACATATAATATCTTTACTGTGTCTTGACATATGAATCATTTAGGGAAGACAATATGGTTTCTGTGAATTTTAAAGACTTCTAATTAATCAGAAGAGTGCTGGATATTGCATAGACTTCTCCACCCTTAGCTGTACTTAGCTGATTTGTGGGTCT-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000187.4(HGD):​c.16-272_87+305del variant causes a splice acceptor, splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a non-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, splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.666

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.053064276 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-120675486-AATGCTCACATCCATGGTGTTCAAGGGGAATATGAGGGATTCTCTTTAACTCTGGATTTTTGGGGATCCTACTGGAAACCCTACAGTTAATTTCACTAGTTTGGATTGGCTGCTGTGCCACCAATCCAATTTTAATCTTTGTGTTGTCATTGCTCTGTATCTTCATTGCCCCTATGACTTGGGAAACCTCTAGACAGTTCACAGGCTAGATTGGAAGAGCCACGGTGGGTGGAGGCACTTTGGCCTGAAAGCTAGTCATCCAGGAATAGGATTCAGAGCTCTTCTAAGCACTTTATTTGCTCATACCTGTCCTTCTGGCAGGGAACCTGGGCAGCGAGGATCCTCTGAAGAACACTCATTCCCAAATCCAGAAATGTACTGTAGGTGACAAAGACACAAATGCCACCATTAGCAGGATTTAAAGAGCATTTCAGAAAATTGGCAGTTTACTAAGGTAAGAATTTCTATATGGACCTATGTTTGTGTATGATGTTCCACATATAATATCTTTACTGTGTCTTGACATATGAATCATTTAGGGAAGACAATATGGTTTCTGTGAATTTTAAAGACTTCTAATTAATCAGAAGAGTGCTGGATATTGCATAGACTTCTCCACCCTTAGCTGTACTTAGCTGATTTGTGGGTCT-A is Pathogenic according to our data. Variant chr3-120675486-AATGCTCACATCCATGGTGTTCAAGGGGAATATGAGGGATTCTCTTTAACTCTGGATTTTTGGGGATCCTACTGGAAACCCTACAGTTAATTTCACTAGTTTGGATTGGCTGCTGTGCCACCAATCCAATTTTAATCTTTGTGTTGTCATTGCTCTGTATCTTCATTGCCCCTATGACTTGGGAAACCTCTAGACAGTTCACAGGCTAGATTGGAAGAGCCACGGTGGGTGGAGGCACTTTGGCCTGAAAGCTAGTCATCCAGGAATAGGATTCAGAGCTCTTCTAAGCACTTTATTTGCTCATACCTGTCCTTCTGGCAGGGAACCTGGGCAGCGAGGATCCTCTGAAGAACACTCATTCCCAAATCCAGAAATGTACTGTAGGTGACAAAGACACAAATGCCACCATTAGCAGGATTTAAAGAGCATTTCAGAAAATTGGCAGTTTACTAAGGTAAGAATTTCTATATGGACCTATGTTTGTGTATGATGTTCCACATATAATATCTTTACTGTGTCTTGACATATGAATCATTTAGGGAAGACAATATGGTTTCTGTGAATTTTAAAGACTTCTAATTAATCAGAAGAGTGCTGGATATTGCATAGACTTCTCCACCCTTAGCTGTACTTAGCTGATTTGTGGGTCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 156275.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGD	NM_000187.4	c.16-272_87+305del		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	2/14	ENST00000283871.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGD	ENST00000283871.10	c.16-272_87+305del		splice_acceptor_variant, splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	2/14	1	NM_000187.4	P1

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:2

Revision: no assertion criteria provided

Submissions by phenotype

Alkaptonuria Pathogenic:2

Pathogenic, no assertion criteria provided	research	Chehab Lab, University of California, San Francisco	-	- -
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:25233259. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00164). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553721650; hg19: chr3-120394333;