19-51713921-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.42

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 Benign. Variant got -10 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_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAS1	NM_001297436.2	c.1240G>A	p.Val414Met	missense_variant	5/5	ENST00000540069.7
HAS1	NM_001523.4	c.1243G>A	p.Val415Met	missense_variant	5/5
HAS1	XM_011526884.3	c.*123G>A		3_prime_UTR_variant	4/4
HAS1	XM_047438719.1	c.*123G>A		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAS1	ENST00000540069.7	c.1240G>A	p.Val414Met	missense_variant	5/5	1	NM_001297436.2	A1

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152242 Hom.: 2 Cov.: 32

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.: 2 AF XY: 0.00435 AC XY: 576 AN XY: 132406

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.: 22 Cov.: 33 AF XY: 0.00479 AC XY: 3474 AN XY: 724568

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.: 2 Cov.: 32 AF XY: 0.00317 AC XY: 236 AN XY: 74508

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.: 5

Bravo AF: 0.00340

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00388 AC: 471

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00646

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	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	T
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

Other links and lift over

dbSNP: rs45625331; hg19: chr19-52217174;