chr19-51717098-G-A

Variant names:

• chr19-51717098-G-A
• rs11084111
• NM_001297436.2:c.795C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001297436.2(HAS1):​c.795C>T​(p.Asp265Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,330 control chromosomes in the GnomAD database, including 11,932 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 0.12 (1392 hom., cov: 32)
  • Exomes 𝑓: 0.10 (10540 hom.)
• Consequence: HAS1 NM_001297436.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.476
• Publications: 15 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=-0.476 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAS1	NM_001297436.2	c.795C>T	p.Asp265Asp	synonymous_variant	Exon 3 of 5	ENST00000540069.7	NP_001284365.1
HAS1	NM_001523.4	c.798C>T	p.Asp266Asp	synonymous_variant	Exon 3 of 5		NP_001514.2
HAS1	XM_011526884.3	c.798C>T	p.Asp266Asp	synonymous_variant	Exon 3 of 4		XP_011525186.1
HAS1	XM_047438719.1	c.795C>T	p.Asp265Asp	synonymous_variant	Exon 3 of 4		XP_047294675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAS1	ENST00000540069.7	c.795C>T	p.Asp265Asp	synonymous_variant	Exon 3 of 5	1	NM_001297436.2	ENSP00000445021.2

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18138 AN: 151878 Hom.: 1388 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0862

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.132 AC: 33100 AN: 251296 AF XY: 0.127

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.445

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.0912

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.104 AC: 152303 AN: 1461334 Hom.: 10540 Cov.: 32 AF XY: 0.104 AC XY: 75575 AN XY: 727028

African (AFR) AF: 0.135 AC: 4515 AN: 33470

American (AMR) AF: 0.120 AC: 5367 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 3549 AN: 26132

East Asian (EAS) AF: 0.429 AC: 17028 AN: 39688

South Asian (SAS) AF: 0.0965 AC: 8327 AN: 86254

European-Finnish (FIN) AF: 0.137 AC: 7306 AN: 53396

Middle Eastern (MID) AF: 0.0933 AC: 538 AN: 5766

European-Non Finnish (NFE) AF: 0.0889 AC: 98799 AN: 1111538

Other (OTH) AF: 0.114 AC: 6874 AN: 60366

GnomAD4 genome AF: 0.120 AC: 18164 AN: 151996 Hom.: 1392 Cov.: 32 AF XY: 0.124 AC XY: 9182 AN XY: 74272

African (AFR) AF: 0.137 AC: 5691 AN: 41420

American (AMR) AF: 0.113 AC: 1722 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 445 AN: 3472

East Asian (EAS) AF: 0.421 AC: 2164 AN: 5138

South Asian (SAS) AF: 0.103 AC: 496 AN: 4820

European-Finnish (FIN) AF: 0.142 AC: 1497 AN: 10564

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0862 AC: 5859 AN: 68006

Other (OTH) AF: 0.124 AC: 261 AN: 2112

Alfa AF: 0.0964 Hom.: 1274

Bravo AF: 0.120

Asia WGS AF: 0.237 AC: 824 AN: 3478

EpiCase AF: 0.0816

EpiControl AF: 0.0858

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.82
DANN	Benign	0.87
PhyloP100		-0.48
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs11084111; hg19: chr19-52220351; COSMIC: COSV55789495; COSMIC: COSV55789495;