NM_001297436.2:c.1240G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001297436.2(HAS1):c.1240G>A(p.Val414Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00466 in 1,608,408 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 22 hom. )

Consequence

HAS1
NM_001297436.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.42

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01144889).

BP6

Variant 19-51713921-C-T is Benign according to our data. Variant chr19-51713921-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 729825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAS1	NM_001297436.2 link	c.1240G>A	p.Val414Met	missense_variant	Exon 5 of 5	ENST00000540069.7	NP_001284365.1	G3V1S7Q8IYH3D2N2G5
HAS1	NM_001523.4 link	c.1243G>A	p.Val415Met	missense_variant	Exon 5 of 5		NP_001514.2	Q92839Q8IYH3D2N2G5
HAS1	XM_011526884.3 link	c.*123G>A		3_prime_UTR_variant	Exon 4 of 4		XP_011525186.1
HAS1	XM_047438719.1 link	c.*123G>A		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 link	c.1240G>A	p.Val414Met	missense_variant	Exon 5 of 5	1	NM_001297436.2	ENSP00000445021.2		G3V1S7

Frequencies

GnomAD3 genomes

AF:

0.00338

AC:

514

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00216

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00506

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00412

AC:

1003

AN:

243154

Hom.:

AF XY:

0.00435

AC XY:

576

AN XY:

132406

show subpopulations

Gnomad AFR exome

AF:

0.000566

Gnomad AMR exome

AF:

0.00337

Gnomad ASJ exome

AF:

0.0185

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00144

Gnomad FIN exome

AF:

0.00275

Gnomad NFE exome

AF:

0.00513

Gnomad OTH exome

AF:

0.00512

GnomAD4 exome

AF:

0.00479

AC:

6980

AN:

1456048

Hom.:

Cov.:

AF XY:

0.00479

AC XY:

3474

AN XY:

724568

show subpopulations

Gnomad4 AFR exome

AF:

0.000806

Gnomad4 AMR exome

AF:

0.00331

Gnomad4 ASJ exome

AF:

0.0172

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00130

Gnomad4 FIN exome

AF:

0.00247

Gnomad4 NFE exome

AF:

0.00525

Gnomad4 OTH exome

AF:

0.00462

GnomAD4 genome

AF:

0.00337

AC:

514

AN:

152360

Hom.:

Cov.:

AF XY:

0.00317

AC XY:

236

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00216

Gnomad4 NFE

AF:

0.00506

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00572

Hom.:

Bravo

AF:

0.00340

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00674

AC:

ExAC

AF:

0.00388

AC:

471

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00646

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

.;T;T

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.8

.;L;.

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.3

.;N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.0080

.;D;D

Sift4G

Uncertain

0.012

D;D;D

Polyphen

1.0, 0.99

.;D;D

Vest4

0.59

MVP

0.62

MPC

0.38

ClinPred

0.015

GERP RS

3.2

Varity_R

0.20

gMVP

0.44

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