chr19-51713866-C-G
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001297436.2(HAS1):āc.1295G>Cā(p.Trp432Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000523 in 1,606,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000079 ( 0 hom., cov: 32)
Exomes š: 0.000050 ( 0 hom. )
Consequence
HAS1
NM_001297436.2 missense
NM_001297436.2 missense
Scores
3
2
9
Clinical Significance
Conservation
PhyloP100: 3.18
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16635966).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HAS1 | NM_001297436.2 | c.1295G>C | p.Trp432Ser | missense_variant | 5/5 | ENST00000540069.7 | |
HAS1 | NM_001523.4 | c.1298G>C | p.Trp433Ser | missense_variant | 5/5 | ||
HAS1 | XM_011526884.3 | c.*178G>C | 3_prime_UTR_variant | 4/4 | |||
HAS1 | XM_047438719.1 | c.*178G>C | 3_prime_UTR_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HAS1 | ENST00000540069.7 | c.1295G>C | p.Trp432Ser | missense_variant | 5/5 | 1 | NM_001297436.2 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152218Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000109 AC: 26AN: 237848Hom.: 0 AF XY: 0.0000691 AC XY: 9AN XY: 130218
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GnomAD4 exome AF: 0.0000495 AC: 72AN: 1454294Hom.: 0 Cov.: 32 AF XY: 0.0000456 AC XY: 33AN XY: 723854
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GnomAD4 genome AF: 0.0000788 AC: 12AN: 152336Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74474
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2024 | The c.1298G>C (p.W433S) alteration is located in exon 5 (coding exon 5) of the HAS1 gene. This alteration results from a G to C substitution at nucleotide position 1298, causing the tryptophan (W) at amino acid position 433 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
Sift4G
Uncertain
D;D;D
Polyphen
0.57, 0.70
.;P;P
Vest4
MutPred
0.60
.;Loss of MoRF binding (P = 0.0771);.;
MVP
MPC
0.16
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at