19-51713677-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001297436.2(HAS1):c.1484T>A(p.Leu495Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,586,368 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 (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

HAS1
NM_001297436.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.93

Variant links:

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]

HAS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32196388).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HAS1	NM_001297436.2 linkuse as main transcript	c.1484T>A	p.Leu495Gln	missense_variant	5/5	ENST00000540069.7
HAS1	NM_001523.4 linkuse as main transcript	c.1487T>A	p.Leu496Gln	missense_variant	5/5
HAS1	XM_011526884.3 linkuse as main transcript	c.*367T>A		3_prime_UTR_variant	4/4
HAS1	XM_047438719.1 linkuse as main transcript	c.*367T>A		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HAS1	ENST00000540069.7 linkuse as main transcript	c.1484T>A	p.Leu495Gln	missense_variant	5/5	1	NM_001297436.2	A1
HAS1	ENST00000601714.5 linkuse as main transcript	c.1508T>A	p.Leu503Gln	missense_variant	4/4	1
HAS1	ENST00000222115.5 linkuse as main transcript	c.1487T>A	p.Leu496Gln	missense_variant	5/5	1		P4

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000365

AC:

AN:

191756

Hom.:

AF XY:

0.0000568

AC XY:

AN XY:

105640

show subpopulations

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:

0.0000862

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000147

AC:

211

AN:

1434134

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

109

AN XY:

711626

show subpopulations

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:

0.000186

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000677

Hom.:

Bravo

AF:

0.0000529

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

Jul 06, 2021

The c.1487T>A (p.L496Q) alteration is located in exon 5 (coding exon 5) of the HAS1 gene. This alteration results from a T to A substitution at nucleotide position 1487, causing the leucine (L) at amino acid position 496 to be replaced by a glutamine (Q). 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

Benign

0.15

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.32

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-0.92

MutationTaster

Benign

0.92

D;D

PrimateAI

Uncertain

0.61

Sift4G

Benign

0.14

T;T;T

Polyphen

0.98, 0.99

.;D;D

Vest4

0.28

MutPred

0.55

.;Gain of sheet (P = 0.0028);.;

MVP

0.52

MPC

0.34

ClinPred

0.53

GERP RS

3.3

Varity_R

0.43

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over