3-50302169-TGCACATACATCTGTGACTTCCCTGTGCCCTCCAGCAC-TCGGGCCACACGGAA

Position:

• chr3-50302169-TGCACATACATCTGTGACTTCCCTGTGCCCTCCAGCAC-TCGGGCCACACGGAA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP3 PP5

The ENST00000447605.2(HYAL1):​c.-26-1_10delinsTTCCGTGTGGCCCG variant causes a splice acceptor, coding sequence, 5 prime UTR 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: HYAL1 ENST00000447605.2 splice_acceptor, coding_sequence, 5_prime_UTR
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.82

Genes affected

HYAL1 (HGNC:5320): (hyaluronidase 1) This gene encodes a lysosomal hyaluronidase. Hyaluronidases intracellularly degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan is thought to be involved in cell proliferation, migration and differentiation. This enzyme is active at an acidic pH and is the major hyaluronidase in plasma. Mutations in this gene are associated with mucopolysaccharidosis type IX, or hyaluronidase deficiency. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.2787194 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of 6, new splice context is: agccgtgccctctatcccAGcat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 3-50302170-GCACATACATCTGTGACTTCCCTGTGCCCTCCAGCAC-CGGGCCACACGGAA is Pathogenic according to our data. Variant chr3-50302170-GCACATACATCTGTGACTTCCCTGTGCCCTCCAGCAC-CGGGCCACACGGAA is described in ClinVar as [Pathogenic]. Clinvar id is 3531.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HYAL1	NM_033159.4	c.751_787delinsTTCCGTGTGGCCCG	p.Val251PhefsTer20	frameshift_variant	2/4	ENST00000395144.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYAL1	ENST00000395144.7	c.751_787delinsTTCCGTGTGGCCCG	p.Val251PhefsTer20	frameshift_variant	2/4	1	NM_033159.4	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:1

Revision: no assertion criteria provided

Submissions by phenotype

Deficiency of hyaluronoglucosaminidase Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 25, 1999

- -

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: rs1553713075; hg19: chr3-50339601;