3-50318160-A-T

Position:

• chr3-50318160-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003773.5(HYAL2):​c.1391T>A​(p.Leu464Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 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)
• Consequence: HYAL2 NM_003773.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYAL2	NM_003773.5	c.1391T>A	p.Leu464Gln	missense_variant	4/4	ENST00000357750.9	NP_003764.3
HYAL2	NM_033158.5	c.1391T>A	p.Leu464Gln	missense_variant	5/5		NP_149348.2
HYAL2	XM_005265524.3	c.1391T>A	p.Leu464Gln	missense_variant	5/5		XP_005265581.1
HYAL2	XM_005265525.3	c.1391T>A	p.Leu464Gln	missense_variant	4/4		XP_005265582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HYAL2	ENST00000357750.9	c.1391T>A	p.Leu464Gln	missense_variant	4/4	1	NM_003773.5	ENSP00000350387.4
HYAL2	ENST00000395139.7	c.1391T>A	p.Leu464Gln	missense_variant	4/4	1		ENSP00000378571.3
HYAL2	ENST00000447092.5	c.1391T>A	p.Leu464Gln	missense_variant	3/3	1		ENSP00000401853.1
HYAL2	ENST00000442581.1	c.1391T>A	p.Leu464Gln	missense_variant	5/5	2		ENSP00000406657.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Oct 14, 2021

The c.1391T>A (p.L464Q) alteration is located in exon 5 (coding exon 3) of the HYAL2 gene. This alteration results from a T to A substitution at nucleotide position 1391, causing the leucine (L) at amino acid position 464 to be replaced by a glutamine (Q). 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	0.16
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T;T;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.59	.;.;.;T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M;M;M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		0.61	P;P;P;P
Vest4		0.53
MutPred		0.54		Gain of catalytic residue at L464 (P = 0.0011);Gain of catalytic residue at L464 (P = 0.0011);Gain of catalytic residue at L464 (P = 0.0011);Gain of catalytic residue at L464 (P = 0.0011);
MVP		0.65
MPC		0.86
ClinPred		0.52	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.82

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: chr3-50355591;