16-69115181-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001199280.2(HAS3):c.1577C>G(p.Ala526Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,588,750 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0043 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (9 hom.)
• Consequence: HAS3 NM_001199280.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.419

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HAS3
• BP4: Computational evidence support a benign effect (MetaRNN=0.006245792).
• BP6: Variant 16-69115181-C-G is Benign according to our data. Variant chr16-69115181-C-G is described in ClinVar as [Benign]. Clinvar id is 731126.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000432 (621/1436548) while in subpopulation AFR AF= 0.0166 (547/32896). AF 95% confidence interval is 0.0155. There are 9 homozygotes in gnomad4_exome. There are 291 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 653 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAS3	NM_001199280.2	c.1577C>G	p.Ala526Gly	missense_variant	4/4	ENST00000569188.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAS3	ENST00000569188.6	c.1577C>G	p.Ala526Gly	missense_variant	4/4	2	NM_001199280.2	P1
HAS3	ENST00000306560.1	c.1577C>G	p.Ala526Gly	missense_variant	4/4	1		P1
HAS3	ENST00000219322.7	c.738+1639C>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00429 AC: 653 AN: 152084 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.0000882

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00123 AC: 281 AN: 228774 Hom.: 3 AF XY: 0.000913 AC XY: 112 AN XY: 122614

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000960

Gnomad OTH exome AF: 0.000183

GnomAD4 exome AF: 0.000432 AC: 621 AN: 1436548 Hom.: 9 Cov.: 34 AF XY: 0.000409 AC XY: 291 AN XY: 711720

Gnomad4 AFR exome AF: 0.0166

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000487

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000637

Gnomad4 OTH exome AF: 0.000726

GnomAD4 genome AF: 0.00431 AC: 656 AN: 152202 Hom.: 8 Cov.: 32 AF XY: 0.00421 AC XY: 313 AN XY: 74394

Gnomad4 AFR AF: 0.0148

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00166 Hom.: 2

Bravo AF: 0.00499

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00134 AC: 162

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.59	D
MetaRNN	Benign	0.0062	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.7	N;N
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.82	P;P
Vest4		0.094
MVP		0.45
MPC		0.83
ClinPred		0.032	T
GERP RS		5.8
Varity_R		0.30
gMVP		0.38

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: rs112187376; hg19: chr16-69149084; COSMIC: COSV104985625; COSMIC: COSV104985625;