chr19-51713558-C-T

Variant names:

• chr19-51713558-C-T
• NM_001297436.2:c.1603G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001297436.2(HAS1):​c.1603G>A​(p.Ala535Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000701 in 1,427,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: HAS1 NM_001297436.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.502
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05110973).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001297436.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAS1	NM_001297436.2	MANE Select	c.1603G>A	p.Ala535Thr	missense	Exon 5 of 5	NP_001284365.1	G3V1S7
	HAS1	NM_001523.4		c.1606G>A	p.Ala536Thr	missense	Exon 5 of 5	NP_001514.2	Q92839

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAS1	ENST00000540069.7	TSL:1 MANE Select	c.1603G>A	p.Ala535Thr	missense	Exon 5 of 5	ENSP00000445021.2	G3V1S7
	HAS1	ENST00000601714.5	TSL:1	c.1627G>A	p.Ala543Thr	missense	Exon 4 of 4	ENSP00000472821.1	M0R2V0
	HAS1	ENST00000222115.5	TSL:1	c.1606G>A	p.Ala536Thr	missense	Exon 5 of 5	ENSP00000222115.1	Q92839

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 179090 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000701 AC: 10 AN: 1427362 Hom.: 0 Cov.: 32 AF XY: 0.00000565 AC XY: 4 AN XY: 707744

African (AFR) AF: 0.00 AC: 0 AN: 32510

American (AMR) AF: 0.00 AC: 0 AN: 40702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25480

East Asian (EAS) AF: 0.00 AC: 0 AN: 37516

South Asian (SAS) AF: 0.00 AC: 0 AN: 83020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000913 AC: 10 AN: 1095790

Other (OTH) AF: 0.00 AC: 0 AN: 58974

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.86
DEOGEN2	Benign	0.070	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.94	N
PhyloP100		0.50
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.077
Sift	Benign	1.0	T
Sift4G	Benign	0.74	T
Polyphen		0.0020	B
Vest4		0.053
MutPred		0.35		Gain of phosphorylation at A536 (P = 0.04)
MVP		0.081
MPC		0.070
ClinPred		0.068	T
GERP RS		2.2
Varity_R		0.029
gMVP		0.24
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

hg19: chr19-52216811;