8-121614529-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_005328.3(HAS2):c.1239C>G(p.Val413=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,998 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (9 hom., cov: 32)
  • Exomes 𝑓: 0.011 (109 hom.)
• Consequence: HAS2 NM_005328.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.852

Genes affected

HAS2 (HGNC:4819): (hyaluronan synthase 2) Hyaluronan or hyaluronic acid (HA) is a high molecular weight unbranched polysaccharide synthesized by a wide variety of organisms from bacteria to mammals, and is a constituent of the extracellular matrix. It consists of alternating glucuronic acid and N-acetylglucosamine residues that are linked by beta-1-3 and beta-1-4 glycosidic bonds. HA is synthesized by membrane-bound synthase at the inner surface of the plasma membrane, and the chains are extruded through pore-like structures into the extracellular space. It serves a variety of functions, including space filling, lubrication of joints, and provision of a matrix through which cells can migrate. HA is actively produced during wound healing and tissue repair to provide a framework for ingrowth of blood vessels and fibroblasts. Changes in the serum concentration of HA are associated with inflammatory and degenerative arthropathies such as rheumatoid arthritis. In addition, the interaction of HA with the leukocyte receptor CD44 is important in tissue-specific homing by leukocytes, and overexpression of HA receptors has been correlated with tumor metastasis. HAS2 is a member of the newly identified vertebrate gene family encoding putative hyaluronan synthases, and its amino acid sequence shows significant homology to glycosaminoglycan synthetase (DG42) from Xenopus laevis, and human and murine hyaluronan synthase 1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 8-121614529-G-C is Benign according to our data. Variant chr8-121614529-G-C is described in ClinVar as [Benign]. Clinvar id is 773404.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.852 with no splicing effect.
• BS2: High AC in GnomAd at 1094 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAS2	NM_005328.3	c.1239C>G	p.Val413=	synonymous_variant	4/4	ENST00000303924.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAS2	ENST00000303924.5	c.1239C>G	p.Val413=	synonymous_variant	4/4	1	NM_005328.3	P1

Frequencies

GnomAD3 genomes AF: 0.00719 AC: 1094 AN: 152150 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00757 AC: 1901 AN: 251012 Hom.: 13 AF XY: 0.00775 AC XY: 1051 AN XY: 135634

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00388

Gnomad ASJ exome AF: 0.0205

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00652

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00866

GnomAD4 exome AF: 0.0113 AC: 16540 AN: 1461730 Hom.: 109 Cov.: 32 AF XY: 0.0109 AC XY: 7918 AN XY: 727174

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.00625

Gnomad4 NFE exome AF: 0.0130

Gnomad4 OTH exome AF: 0.0118

GnomAD4 genome AF: 0.00718 AC: 1094 AN: 152268 Hom.: 9 Cov.: 32 AF XY: 0.00655 AC XY: 488 AN XY: 74448

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0112 Hom.: 1

Bravo AF: 0.00750

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0135

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	4.8
Dann	Benign	0.71

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: rs75735654; hg19: chr8-122626769;