rs709210

Variant names:

• chr3-50320438-A-C
• rs709210
• NM_003773.5:c.52T>G

Your query was ambiguous. Multiple possible variants found:

• chr3-50320438-A-C
• chr3-50320438-A-G
• chr3-50320438-A-T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S18T) has been classified as Uncertain significance.

• 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
• Publications: 43 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003773.5. 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
	HYAL2	NM_003773.5	MANE Select	c.52T>G	p.Ser18Ala	missense	Exon 2 of 4	NP_003764.3
	HYAL2	NM_033158.5		c.52T>G	p.Ser18Ala	missense	Exon 3 of 5	NP_149348.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYAL2	ENST00000357750.9	TSL:1 MANE Select	c.52T>G	p.Ser18Ala	missense	Exon 2 of 4	ENSP00000350387.4	Q12891
	HYAL2	ENST00000395139.7	TSL:1	c.52T>G	p.Ser18Ala	missense	Exon 2 of 4	ENSP00000378571.3	Q12891
	HYAL2	ENST00000447092.5	TSL:1	c.52T>G	p.Ser18Ala	missense	Exon 1 of 3	ENSP00000401853.1	Q12891

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

GnomAD2 exomes AF: 0.676 AC: 152703 AN: 225886 AF XY: 0.654

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 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

African (AFR) AF: 0.900 AC: 29779 AN: 33080

American (AMR) AF: 0.841 AC: 36035 AN: 42832

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 15582 AN: 24086

East Asian (EAS) AF: 0.793 AC: 31224 AN: 39390

South Asian (SAS) AF: 0.424 AC: 34641 AN: 81712

European-Finnish (FIN) AF: 0.627 AC: 32066 AN: 51182

Middle Eastern (MID) AF: 0.626 AC: 3489 AN: 5570

European-Non Finnish (NFE) AF: 0.642 AC: 703458 AN: 1095990

Other (OTH) AF: 0.661 AC: 39035 AN: 59058

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

African (AFR) AF: 0.888 AC: 36934 AN: 41586

American (AMR) AF: 0.808 AC: 12371 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2248 AN: 3472

East Asian (EAS) AF: 0.773 AC: 3993 AN: 5164

South Asian (SAS) AF: 0.416 AC: 2008 AN: 4826

European-Finnish (FIN) AF: 0.626 AC: 6638 AN: 10606

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.637 AC: 43350 AN: 68006

Other (OTH) AF: 0.737 AC: 1560 AN: 2116

Alfa AF: 0.675 Hom.: 34863

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.031	T
MetaRNN	Benign	6.1e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.99	N
PhyloP100		0.0070
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.068
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.41
ClinPred		0.00087	T
GERP RS		3.7
Varity_R		0.049
gMVP		0.27
Mutation Taster		=100/0	polymorphism (auto)

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