3-50318278-AGT-A

Position:

• chr3-50318278-AGT-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_003773.5(HYAL2):​c.1271_1272delAC​(p.His424fs) variant causes a frameshift 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: HYAL2 NM_003773.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.51

Genes affected

HYAL2 (HGNC:5321): (hyaluronidase 2) This gene encodes a weak acid-active hyaluronidase. The encoded protein is similar in structure to other more active hyaluronidases. Hyaluronidases degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan and fragments of hyaluronan are thought to be involved in cell proliferation, migration and differentiation. Although it was previously thought to be a lysosomal hyaluronidase that is active at a pH below 4, the encoded protein is likely a GPI-anchored cell surface protein. This hyaluronidase serves as a receptor for the oncogenic virus Jaagsiekte sheep retrovirus. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. This gene encodes two alternatively spliced transcript variants which differ only in the 5' UTR.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.106 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-50318278-AGT-A is Pathogenic according to our data. Variant chr3-50318278-AGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 1065396.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYAL2	NM_003773.5	c.1271_1272delAC	p.His424fs	frameshift_variant	4/4	ENST00000357750.9	NP_003764.3
HYAL2	NM_033158.5	c.1271_1272delAC	p.His424fs	frameshift_variant	5/5		NP_149348.2
HYAL2	XM_005265524.3	c.1271_1272delAC	p.His424fs	frameshift_variant	5/5		XP_005265581.1
HYAL2	XM_005265525.3	c.1271_1272delAC	p.His424fs	frameshift_variant	4/4		XP_005265582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HYAL2	ENST00000357750.9	c.1271_1272delAC	p.His424fs	frameshift_variant	4/4	1	NM_003773.5	ENSP00000350387.4
HYAL2	ENST00000395139.7	c.1271_1272delAC	p.His424fs	frameshift_variant	4/4	1		ENSP00000378571.3
HYAL2	ENST00000447092.5	c.1271_1272delAC	p.His424fs	frameshift_variant	3/3	1		ENSP00000401853.1
HYAL2	ENST00000442581.1	c.1271_1272delAC	p.His424fs	frameshift_variant	5/5	2		ENSP00000406657.1

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

HYAL2 deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

research

New Leaf Center

Dec 09, 2021

From Fasham et al. 2021: Functional assays demonstrating a variant has abnormal protein function. Truncating variant expected not to undergo nonsense mediated decay. Absent from gnomAD databases. In trans with p.(Leu238Arg) . A strong consensus supporting a clinical diagnosis with a specific phenotype. -

MUGGENTHALER-CHOWDHURY-CHIOZA SYNDROME Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2025

- -

Computational scores

Source: dbNSFP v4.3

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: chr3-50355709;