NM_001297436.2:c.1308C>G

Variant names:

• chr19-51713853-G-C
• rs540354288
• NM_001297436.2:c.1308C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001297436.2(HAS1):​c.1308C>G​(p.Cys436Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HAS1 NM_001297436.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.434

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAS1	NM_001297436.2	c.1308C>G	p.Cys436Trp	missense_variant	Exon 5 of 5	ENST00000540069.7	NP_001284365.1
HAS1	NM_001523.4	c.1311C>G	p.Cys437Trp	missense_variant	Exon 5 of 5		NP_001514.2
HAS1	XM_011526884.3	c.*191C>G		3_prime_UTR_variant	Exon 4 of 4		XP_011525186.1
HAS1	XM_047438719.1	c.*191C>G		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.1308C>G	p.Cys436Trp	missense_variant	Exon 5 of 5	1	NM_001297436.2	ENSP00000445021.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000422 AC: 1 AN: 236714 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS 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: 6.88e-7 AC: 1 AN: 1454386 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1311C>G (p.C437W) alteration is located in exon 5 (coding exon 5) of the HAS1 gene. This alteration results from a C to G substitution at nucleotide position 1311, causing the cysteine (C) at amino acid position 437 to be replaced by a tryptophan (W). 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	Pathogenic	0.90
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	.;D;T
Eigen	Benign	-0.036
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;L;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-5.1	.;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0050	.;D;D
Sift4G	Uncertain	0.059	T;T;T
Polyphen		0.99, 1.0	.;D;D
Vest4		0.56
MutPred		0.59		.;Gain of catalytic residue at L435 (P = 0.0026);.;
MVP		0.48
MPC		0.45
ClinPred		0.99	D
GERP RS		-0.33
Varity_R		0.60
gMVP		0.82

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: rs540354288; hg19: chr19-52217106;