dbSNP rs374428400: HAS3:p.Arg83Trp (chr16-69109642-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001199280.2(HAS3):c.247C>T(p.Arg83Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,610,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

HAS3
NM_001199280.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.773

Variant links:

Genes affected

HAS3 (HGNC:4820): (hyaluronan synthase 3) The protein encoded by this gene is involved in the synthesis of the unbranched glycosaminoglycan hyaluronan, or hyaluronic acid, which is a major constituent of the extracellular matrix. This gene is a member of the NODC/HAS gene family. Compared to the proteins encoded by other members of this gene family, this protein appears to be more of a regulator of hyaluronan synthesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]

HAS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11755663).

BS2

High AC in GnomAdExome4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAS3	NM_001199280.2 link	c.247C>T	p.Arg83Trp	missense_variant	Exon 2 of 4	ENST00000569188.6	NP_001186209.1	O00219-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HAS3	ENST00000569188.6 link	c.247C>T	p.Arg83Trp	missense_variant	Exon 2 of 4	2	NM_001199280.2	ENSP00000454731.1	O00219-1
HAS3	ENST00000306560.1 link	c.247C>T	p.Arg83Trp	missense_variant	Exon 2 of 4	1		ENSP00000304440.1	O00219-1
HAS3	ENST00000219322.7 link	c.247C>T	p.Arg83Trp	missense_variant	Exon 2 of 4	1		ENSP00000219322.3	O00219-2
HAS3	ENST00000566118.5 link	c.247C>T	p.Arg83Trp	missense_variant	Exon 2 of 4	5		ENSP00000456246.1	H3BRH5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000244

AC:

AN:

246272

Hom.:

AF XY:

0.00000748

AC XY:

AN XY:

133680

show subpopulations

Gnomad AFR exome

AF:

0.0000627

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000548

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000370

AC:

AN:

1457782

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

725340

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000455

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.247C>T (p.R83W) alteration is located in exon 2 (coding exon 1) of the HAS3 gene. This alteration results from a C to T substitution at nucleotide position 247, causing the arginine (R) at amino acid position 83 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

Benign

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.;T;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.73

.;T;T;T

M_CAP

Benign

0.077

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;N;.;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.19

T;T;T;T

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.90

P;P;.;P

Vest4

0.23

MVP

0.076

MPC

0.92

ClinPred

0.051

GERP RS

-3.7

Varity_R

0.034

gMVP

0.67

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