3-50294947-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_003549.4(HYAL3):c.656G>A(p.Arg219His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000878 in 1,606,190 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: HYAL3 NM_003549.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.606

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022292018).
• BP6: Variant 3-50294947-C-T is Benign according to our data. Variant chr3-50294947-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2209089.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HYAL3	NM_003549.4	c.656G>A	p.Arg219His	missense_variant	2/4	ENST00000336307.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYAL3	ENST00000336307.6	c.656G>A	p.Arg219His	missense_variant	2/4	1	NM_003549.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000129 AC: 32 AN: 248184 Hom.: 0 AF XY: 0.000119 AC XY: 16 AN XY: 134444

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.000404

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000987

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000887 AC: 129 AN: 1453874 Hom.: 0 Cov.: 30 AF XY: 0.0000914 AC XY: 66 AN XY: 721720

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000899

Gnomad4 ASJ exome AF: 0.000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000723

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74472

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000204 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.0
Dann	Benign	0.70
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.031	N
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.022	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.030	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.45	N;N;.;N
REVEL	Benign	0.068
Sift	Benign	0.59	T;T;.;T
Sift4G	Benign	0.74	T;T;T;T
Polyphen		0.0070	B;B;B;B
Vest4		0.056
MVP		0.072
MPC		0.40
ClinPred		0.0036	T
GERP RS		-5.1
Varity_R		0.025
gMVP		0.51

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: rs142315421; hg19: chr3-50332378; COSMIC: COSV56497173; COSMIC: COSV56497173;