chr19-51713623-A-G

Variant names:

• chr19-51713623-A-G
• rs1332449531
• NM_001297436.2:c.1538T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001297436.2(HAS1):​c.1538T>C​(p.Leu513Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,407,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HAS1 NM_001297436.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.90

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAS1	NM_001297436.2	c.1538T>C	p.Leu513Pro	missense_variant	Exon 5 of 5	ENST00000540069.7	NP_001284365.1
HAS1	NM_001523.4	c.1541T>C	p.Leu514Pro	missense_variant	Exon 5 of 5		NP_001514.2
HAS1	XM_011526884.3	c.*421T>C		3_prime_UTR_variant	Exon 4 of 4		XP_011525186.1
HAS1	XM_047438719.1	c.*421T>C		3_prime_UTR_variant	Exon 4 of 4		XP_047294675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAS1	ENST00000540069.7	c.1538T>C	p.Leu513Pro	missense_variant	Exon 5 of 5	1	NM_001297436.2	ENSP00000445021.2
HAS1	ENST00000601714.5	c.1562T>C	p.Leu521Pro	missense_variant	Exon 4 of 4	1		ENSP00000472821.1
HAS1	ENST00000222115.5	c.1541T>C	p.Leu514Pro	missense_variant	Exon 5 of 5	1		ENSP00000222115.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000626 AC: 1 AN: 159868 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 87216

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000160

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1407982 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 695840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.22e-7

Gnomad4 OTH exome AF: 0.0000343

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1541T>C (p.L514P) alteration is located in exon 5 (coding exon 5) of the HAS1 gene. This alteration results from a T to C substitution at nucleotide position 1541, causing the leucine (L) at amino acid position 514 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;D;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	.;M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.3	.;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0080	.;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.88
MutPred		0.72		.;Loss of stability (P = 0.0199);.;
MVP		0.58
MPC		0.51
ClinPred		0.96	D
GERP RS		3.1
Varity_R		0.79
gMVP		0.76

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: rs1332449531; hg19: chr19-52216876;