19-51717098-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001297436.2(HAS1):​c.795C>G​(p.Asp265Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HAS1 NM_001297436.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.476
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAS1	NM_001297436.2	c.795C>G	p.Asp265Glu	missense_variant	Exon 3 of 5	ENST00000540069.7	NP_001284365.1
HAS1	NM_001523.4	c.798C>G	p.Asp266Glu	missense_variant	Exon 3 of 5		NP_001514.2
HAS1	XM_011526884.3	c.798C>G	p.Asp266Glu	missense_variant	Exon 3 of 4		XP_011525186.1
HAS1	XM_047438719.1	c.795C>G	p.Asp265Glu	missense_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>G	p.Asp265Glu	missense_variant	Exon 3 of 5	1	NM_001297436.2	ENSP00000445021.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461650 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111816

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	5.7
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.64	T;T;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.1	.;L;.;.
PhyloP100		-0.48
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.1	.;D;D;.
REVEL	Benign	0.21
Sift	Benign	0.22	.;T;T;.
Sift4G	Benign	0.073	T;T;T;T
Polyphen		0.97, 0.99	.;D;D;.
Vest4		0.75
MutPred		0.54		.;Loss of sheet (P = 0.0817);.;.;
MVP		0.43
MPC		0.38
ClinPred		0.99	D
GERP RS		-2.1
Varity_R		0.25
gMVP		0.39
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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;