3-50295266-G-A

Position:

• chr3-50295266-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000336307.6(HYAL3):​c.337C>T​(p.His113Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,613,800 control chromosomes in the GnomAD database, including 157,583 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.35 (11198 hom., cov: 34)
  • Exomes 𝑓: 0.44 (146385 hom.)
• Consequence: HYAL3 ENST00000336307.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.447

Genes affected

HYAL3 (HGNC:5322): (hyaluronidase 3) This gene encodes a member of the hyaluronidase family. Hyaluronidases are endoglycosidase enzymes that degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. The regulated turnover of hyaluronan plays a critical role in many biological processes including cell proliferation, migration and differentiation. The encoded protein may also play an important role in sperm function. This gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression, and the expression of specific transcript variants may be indicative of tumor status. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and some isoforms may lack hyaluronidase activity. This gene overlaps and is on the same strand as N-acetyltransferase 6 (GCN5-related), and some transcripts of each gene share a portion of the first exon. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.1286478E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYAL3	NM_003549.4	c.337C>T	p.His113Tyr	missense_variant	2/4	ENST00000336307.6	NP_003540.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HYAL3	ENST00000336307.6	c.337C>T	p.His113Tyr	missense_variant	2/4	1	NM_003549.4	ENSP00000337425	P1

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53554 AN: 152144 Hom.: 11191 Cov.: 34

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.0908

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.392

GnomAD3 exomes AF: 0.369 AC: 92728 AN: 251198 Hom.: 19327 AF XY: 0.374 AC XY: 50852 AN XY: 135804

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.0901

Gnomad SAS exome AF: 0.258

Gnomad FIN exome AF: 0.424

Gnomad NFE exome AF: 0.478

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.437 AC: 638924 AN: 1461536 Hom.: 146385 Cov.: 61 AF XY: 0.433 AC XY: 315036 AN XY: 727090

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.311

Gnomad4 ASJ exome AF: 0.423

Gnomad4 EAS exome AF: 0.130

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.423

Gnomad4 NFE exome AF: 0.479

Gnomad4 OTH exome AF: 0.405

GnomAD4 genome AF: 0.352 AC: 53562 AN: 152264 Hom.: 11198 Cov.: 34 AF XY: 0.345 AC XY: 25714 AN XY: 74436

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.366

Gnomad4 ASJ AF: 0.436

Gnomad4 EAS AF: 0.0903

Gnomad4 SAS AF: 0.241

Gnomad4 FIN AF: 0.426

Gnomad4 NFE AF: 0.476

Gnomad4 OTH AF: 0.393

Alfa AF: 0.447 Hom.: 27564

Bravo AF: 0.341

TwinsUK AF: 0.474 AC: 1758

ALSPAC AF: 0.490 AC: 1887

ESP6500AA AF: 0.165 AC: 727

ESP6500EA AF: 0.484 AC: 4163

ExAC AF: 0.369 AC: 44756

Asia WGS AF: 0.212 AC: 742 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.83
DEOGEN2	Benign	0.18	.;T;T;.;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.34	.;.;T;T;T
MetaRNN	Benign	0.00031	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L;L;L;L;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N;N;.;N;N
REVEL	Benign	0.036
Sift	Benign	0.29	T;T;.;T;T
Sift4G	Benign	0.32	T;T;T;T;.
Polyphen		0.30	B;P;P;B;.
Vest4		0.10
MPC		0.66
ClinPred		0.0066	T
GERP RS		1.6
Varity_R		0.098
gMVP		0.50

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: rs13100173; hg19: chr3-50332697; COSMIC: COSV56497193; COSMIC: COSV56497193;