3-50318200-C-T

Position:

• chr3-50318200-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003773.5(HYAL2):​c.1351G>A​(p.Glu451Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: HYAL2 NM_003773.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.169

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04272321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYAL2	NM_003773.5	c.1351G>A	p.Glu451Lys	missense_variant	4/4	ENST00000357750.9	NP_003764.3
HYAL2	NM_033158.5	c.1351G>A	p.Glu451Lys	missense_variant	5/5		NP_149348.2
HYAL2	XM_005265524.3	c.1351G>A	p.Glu451Lys	missense_variant	5/5		XP_005265581.1
HYAL2	XM_005265525.3	c.1351G>A	p.Glu451Lys	missense_variant	4/4		XP_005265582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HYAL2	ENST00000357750.9	c.1351G>A	p.Glu451Lys	missense_variant	4/4	1	NM_003773.5	ENSP00000350387.4
HYAL2	ENST00000395139.7	c.1351G>A	p.Glu451Lys	missense_variant	4/4	1		ENSP00000378571.3
HYAL2	ENST00000447092.5	c.1351G>A	p.Glu451Lys	missense_variant	3/3	1		ENSP00000401853.1
HYAL2	ENST00000442581.1	c.1351G>A	p.Glu451Lys	missense_variant	5/5	2		ENSP00000406657.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249538 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460470 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726516

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.1351G>A (p.E451K) alteration is located in exon 5 (coding exon 3) of the HYAL2 gene. This alteration results from a G to A substitution at nucleotide position 1351, causing the glutamic acid (E) at amino acid position 451 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.62
DANN	Benign	0.51
DEOGEN2	Benign	0.21	T;T;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.76	.;.;.;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.043	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.48	N;N;N;N
REVEL	Benign	0.017
Sift	Benign	0.91	T;T;T;T
Sift4G	Benign	0.95	T;T;T;T
Polyphen		0.0080	B;B;B;B
Vest4		0.20
MutPred		0.31		Gain of ubiquitination at E451 (P = 0.0146);Gain of ubiquitination at E451 (P = 0.0146);Gain of ubiquitination at E451 (P = 0.0146);Gain of ubiquitination at E451 (P = 0.0146);
MVP		0.36
MPC		0.57
ClinPred		0.0062	T
GERP RS		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.46

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: rs373307469; hg19: chr3-50355631; COSMIC: COSV63305883; COSMIC: COSV63305883;