19-51716824-C-T

Position:

• chr19-51716824-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000540069.7(HAS1):​c.925+144G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 675,066 control chromosomes in the GnomAD database, including 174,180 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.67 (34916 hom., cov: 29)
  • Exomes 𝑓: 0.73 (139264 hom.)
• Consequence: HAS1 ENST00000540069.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0530

Genes affected

HAS1 (HGNC:4818): (hyaluronan synthase 1) 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. HAS1 is a member of the newly identified vertebrate gene family encoding putative hyaluronan synthases, and its amino acid sequence shows significant homology to the hasA gene product of Streptococcus pyogenes, a glycosaminoglycan synthetase (DG42) from Xenopus laevis, and a recently described murine hyaluronan synthase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAS1	NM_001297436.2	c.925+144G>A		intron_variant		ENST00000540069.7	NP_001284365.1
HAS1	NM_001523.4	c.928+144G>A		intron_variant			NP_001514.2
HAS1	XM_011526884.3	c.928+144G>A		intron_variant			XP_011525186.1
HAS1	XM_047438719.1	c.925+144G>A		intron_variant			XP_047294675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAS1	ENST00000540069.7	c.925+144G>A		intron_variant		1	NM_001297436.2	ENSP00000445021	A1

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101598 AN: 151682 Hom.: 34885 Cov.: 29

Gnomad AFR AF: 0.521

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.873

Gnomad SAS AF: 0.755

Gnomad FIN AF: 0.797

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.651

GnomAD4 exome AF: 0.725 AC: 379525 AN: 523266 Hom.: 139264 AF XY: 0.726 AC XY: 201438 AN XY: 277634

Gnomad4 AFR exome AF: 0.506

Gnomad4 AMR exome AF: 0.813

Gnomad4 ASJ exome AF: 0.692

Gnomad4 EAS exome AF: 0.902

Gnomad4 SAS exome AF: 0.760

Gnomad4 FIN exome AF: 0.785

Gnomad4 NFE exome AF: 0.700

Gnomad4 OTH exome AF: 0.706

GnomAD4 genome AF: 0.670 AC: 101683 AN: 151800 Hom.: 34916 Cov.: 29 AF XY: 0.678 AC XY: 50284 AN XY: 74188

Gnomad4 AFR AF: 0.521

Gnomad4 AMR AF: 0.750

Gnomad4 ASJ AF: 0.693

Gnomad4 EAS AF: 0.873

Gnomad4 SAS AF: 0.755

Gnomad4 FIN AF: 0.797

Gnomad4 NFE AF: 0.702

Gnomad4 OTH AF: 0.654

Alfa AF: 0.612 Hom.: 1793

Bravo AF: 0.674

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.65
DANN	Benign	0.68

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: rs11084110; hg19: chr19-52220077;