3-50318419-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_003773.5(HYAL2):c.1132C>T(p.Arg378Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: HYAL2 NM_003773.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.70

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• PP5: Variant 3-50318419-G-A is Pathogenic according to our data. Variant chr3-50318419-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1065395.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HYAL2	NM_003773.5	c.1132C>T	p.Arg378Cys	missense_variant	4/4	ENST00000357750.9
HYAL2	NM_033158.5	c.1132C>T	p.Arg378Cys	missense_variant	5/5
HYAL2	XM_005265524.3	c.1132C>T	p.Arg378Cys	missense_variant	5/5
HYAL2	XM_005265525.3	c.1132C>T	p.Arg378Cys	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYAL2	ENST00000357750.9	c.1132C>T	p.Arg378Cys	missense_variant	4/4	1	NM_003773.5	P1
HYAL2	ENST00000395139.7	c.1132C>T	p.Arg378Cys	missense_variant	4/4	1		P1
HYAL2	ENST00000447092.5	c.1132C>T	p.Arg378Cys	missense_variant	3/3	1		P1
HYAL2	ENST00000442581.1	c.1132C>T	p.Arg378Cys	missense_variant	5/5	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250238 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135656

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460880 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726766

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

HYAL2 deficiency Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

New Leaf Center

Dec 09, 2021

From Fasham et al. 2021: At extremely low frequency in gnomAD databases. In trans with p.(Ala64Thr). Cosegregation with disease in multiple affected family members (≤1/16). In silico missense prediction tools support a deleterious effect on the gene or gene product. A strong consensus supporting a clinical diagnosis with a specific phenotype. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.4	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.9	D;D;D;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.80
MutPred		0.65		Loss of catalytic residue at R378 (P = 0.01);Loss of catalytic residue at R378 (P = 0.01);Loss of catalytic residue at R378 (P = 0.01);Loss of catalytic residue at R378 (P = 0.01);
MVP		0.82
MPC		1.7
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.93

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

LitVar

Other links and lift over

dbSNP: rs1553715895; hg19: chr3-50355850; COSMIC: COSV63306325; COSMIC: COSV63306325;