Genetic Variant NM_003773.5:c.1412G>A (chr3-50318139-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_003773.5(HYAL2):c.1412G>A(p.Trp471*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,413,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

HYAL2
NM_003773.5 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.151

Variant links:

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]

HYAL2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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 0.00703 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYAL2	NM_003773.5 link	c.1412G>A	p.Trp471*	stop_gained	Exon 4 of 4	ENST00000357750.9	NP_003764.3	Q12891
HYAL2	NM_033158.5 link	c.1412G>A	p.Trp471*	stop_gained	Exon 5 of 5		NP_149348.2	Q12891
HYAL2	XM_005265524.3 link	c.1412G>A	p.Trp471*	stop_gained	Exon 5 of 5		XP_005265581.1	Q12891
HYAL2	XM_005265525.3 link	c.1412G>A	p.Trp471*	stop_gained	Exon 4 of 4		XP_005265582.1	Q12891

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HYAL2	ENST00000357750.9 link	c.1412G>A	p.Trp471*	stop_gained	Exon 4 of 4	1	NM_003773.5	ENSP00000350387.4	Q12891
HYAL2	ENST00000395139.7 link	c.1412G>A	p.Trp471*	stop_gained	Exon 4 of 4	1		ENSP00000378571.3	Q12891
HYAL2	ENST00000447092.5 link	c.1412G>A	p.Trp471*	stop_gained	Exon 3 of 3	1		ENSP00000401853.1	Q12891
HYAL2	ENST00000442581.1 link	c.1412G>A	p.Trp471*	stop_gained	Exon 5 of 5	2		ENSP00000406657.1	Q12891

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000467

AC:

AN:

214348

Hom.:

AF XY:

0.00

AC XY:

AN XY:

114662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000566

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:

7.07e-7

AC:

AN:

1413824

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697636

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.30

Vest4

0.60

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over