3-50320438-A-C

Position:

• chr3-50320438-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003773.5(HYAL2):​c.52T>G​(p.Ser18Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 1,585,186 control chromosomes in the GnomAD database, including 344,347 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.72 (40928 hom., cov: 35)
  • Exomes 𝑓: 0.65 (303419 hom.)
• Consequence: HYAL2 NM_003773.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00700

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]

TUSC2 (HGNC:17034): (tumor suppressor 2, mitochondrial calcium regulator) Predicted to be involved in inflammatory response and regulation of mitochondrial membrane potential. Predicted to act upstream of or within several processes, including natural killer cell differentiation; neutrophil-mediated killing of gram-negative bacterium; and regulation of cytokine production. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.116206E-7).
• BP6: Variant 3-50320438-A-C is Benign according to our data. Variant chr3-50320438-A-C is described in ClinVar as [Benign]. Clinvar id is 1183695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYAL2	NM_003773.5	c.52T>G	p.Ser18Ala	missense_variant	2/4	ENST00000357750.9	NP_003764.3
HYAL2	NM_033158.5	c.52T>G	p.Ser18Ala	missense_variant	3/5		NP_149348.2
HYAL2	XM_005265524.3	c.52T>G	p.Ser18Ala	missense_variant	3/5		XP_005265581.1
HYAL2	XM_005265525.3	c.52T>G	p.Ser18Ala	missense_variant	2/4		XP_005265582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HYAL2	ENST00000357750.9	c.52T>G	p.Ser18Ala	missense_variant	2/4	1	NM_003773.5	ENSP00000350387	P1

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109799 AN: 152168 Hom.: 40867 Cov.: 35

Gnomad AFR AF: 0.888

Gnomad AMI AF: 0.676

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.734

GnomAD3 exomes AF: 0.676 AC: 152703 AN: 225886 Hom.: 53332 AF XY: 0.654 AC XY: 79723 AN XY: 121846

Gnomad AFR exome AF: 0.894

Gnomad AMR exome AF: 0.850

Gnomad ASJ exome AF: 0.648

Gnomad EAS exome AF: 0.771

Gnomad SAS exome AF: 0.424

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.646

Gnomad OTH exome AF: 0.660

GnomAD4 exome AF: 0.646 AC: 925309 AN: 1432900 Hom.: 303419 Cov.: 69 AF XY: 0.638 AC XY: 452717 AN XY: 709376

Gnomad4 AFR exome AF: 0.900

Gnomad4 AMR exome AF: 0.841

Gnomad4 ASJ exome AF: 0.647

Gnomad4 EAS exome AF: 0.793

Gnomad4 SAS exome AF: 0.424

Gnomad4 FIN exome AF: 0.627

Gnomad4 NFE exome AF: 0.642

Gnomad4 OTH exome AF: 0.661

GnomAD4 genome AF: 0.722 AC: 109920 AN: 152286 Hom.: 40928 Cov.: 35 AF XY: 0.716 AC XY: 53306 AN XY: 74464

Gnomad4 AFR AF: 0.888

Gnomad4 AMR AF: 0.808

Gnomad4 ASJ AF: 0.647

Gnomad4 EAS AF: 0.773

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.626

Gnomad4 NFE AF: 0.637

Gnomad4 OTH AF: 0.737

Alfa AF: 0.667 Hom.: 23969

Bravo AF: 0.752

TwinsUK AF: 0.652 AC: 2416

ALSPAC AF: 0.646 AC: 2488

ESP6500AA AF: 0.883 AC: 3883

ESP6500EA AF: 0.644 AC: 5541

ExAC AF: 0.656 AC: 79203

Asia WGS AF: 0.581 AC: 2024 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.56
DEOGEN2	Benign	0.20	T;T;T;T;.;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.031	.;.;.;T;T;T;T;T;T
MetaRNN	Benign	6.1e-7	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.99	N;N;N;N;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.27	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.068
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;.;.;.;.
Polyphen		0.0	B;B;B;B;.;.;.;.;.
Vest4		0.019
MPC		0.41
ClinPred		0.00087	T
GERP RS		3.7
Varity_R		0.049
gMVP		0.27

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: rs709210; hg19: chr3-50357869; COSMIC: COSV51700161; COSMIC: COSV51700161;