rs35455589

Positions:

• chr3-50318299-T-A
• chr3-50318299-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003773.5(HYAL2):​c.1252A>T​(p.Ile418Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,190 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I418L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HYAL2 NM_003773.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.344

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09396681).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYAL2	NM_003773.5	c.1252A>T	p.Ile418Phe	missense_variant	4/4	ENST00000357750.9	NP_003764.3
HYAL2	NM_033158.5	c.1252A>T	p.Ile418Phe	missense_variant	5/5		NP_149348.2
HYAL2	XM_005265524.3	c.1252A>T	p.Ile418Phe	missense_variant	5/5		XP_005265581.1
HYAL2	XM_005265525.3	c.1252A>T	p.Ile418Phe	missense_variant	4/4		XP_005265582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HYAL2	ENST00000357750.9	c.1252A>T	p.Ile418Phe	missense_variant	4/4	1	NM_003773.5	ENSP00000350387.4
HYAL2	ENST00000395139.7	c.1252A>T	p.Ile418Phe	missense_variant	4/4	1		ENSP00000378571.3
HYAL2	ENST00000447092.5	c.1252A>T	p.Ile418Phe	missense_variant	3/3	1		ENSP00000401853.1
HYAL2	ENST00000442581.1	c.1252A>T	p.Ile418Phe	missense_variant	5/5	2		ENSP00000406657.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250792 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

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: 0.00000205 AC: 3 AN: 1461190 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726914

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.40	T;T;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.091
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.36	.;.;.;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.094	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L;L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.25	T;T;T;T
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.070	B;B;B;B
Vest4		0.075
MutPred		0.50		Loss of stability (P = 0.1164);Loss of stability (P = 0.1164);Loss of stability (P = 0.1164);Loss of stability (P = 0.1164);
MVP		0.68
MPC		0.83
ClinPred		0.18	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.64

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: rs35455589; hg19: chr3-50355730;