chr3-50294746-C-T

Variant names:

• chr3-50294746-C-T
• rs781817037
• NM_003549.4:c.857G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003549.4(HYAL3):​c.857G>A​(p.Arg286His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,507,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: HYAL3 NM_003549.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003549.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYAL3	NM_003549.4	MANE Select	c.857G>A	p.Arg286His	missense	Exon 2 of 4	NP_003540.2
	HYAL3	NM_001200029.2		c.857G>A	p.Arg286His	missense	Exon 2 of 4	NP_001186958.1	O43820-1
	HYAL3	NM_001200030.2		c.857G>A	p.Arg286His	missense	Exon 2 of 3	NP_001186959.1	O43820-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYAL3	ENST00000336307.6	TSL:1 MANE Select	c.857G>A	p.Arg286His	missense	Exon 2 of 4	ENSP00000337425.1	O43820-1
	HYAL3	ENST00000450982.6	TSL:1	c.857G>A	p.Arg286His	missense	Exon 2 of 3	ENSP00000391922.1	O43820-2
	HYAL3	ENST00000415204.5	TSL:1	c.110G>A	p.Arg37His	missense	Exon 2 of 4	ENSP00000401092.1	O43820-3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000283 AC: 5 AN: 176876 AF XY: 0.0000215

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000959 AC: 13 AN: 1355764 Hom.: 0 Cov.: 30 AF XY: 0.00000755 AC XY: 5 AN XY: 662310

African (AFR) AF: 0.0000997 AC: 3 AN: 30100

American (AMR) AF: 0.000140 AC: 4 AN: 28654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19720

East Asian (EAS) AF: 0.00 AC: 0 AN: 38590

South Asian (SAS) AF: 0.0000145 AC: 1 AN: 68884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5256

European-Non Finnish (NFE) AF: 0.00000377 AC: 4 AN: 1059658

Other (OTH) AF: 0.0000180 AC: 1 AN: 55664

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74358

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000176 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		2.4
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.82		Loss of MoRF binding (P = 0.0065)
MVP		0.30
MPC		1.2
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.67
gMVP		0.83
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs781817037; hg19: chr3-50332177;