chr16-69109912-C-T

Variant names:

• chr16-69109912-C-T
• rs751988494
• NM_001199280.2:c.517C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001199280.2(HAS3):​c.517C>T​(p.Arg173Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,914 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R173H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: HAS3 NM_001199280.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3640839).
• BS2: High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAS3	NM_001199280.2	c.517C>T	p.Arg173Cys	missense_variant	Exon 2 of 4	ENST00000569188.6	NP_001186209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAS3	ENST00000569188.6	c.517C>T	p.Arg173Cys	missense_variant	Exon 2 of 4	2	NM_001199280.2	ENSP00000454731.1
HAS3	ENST00000306560.1	c.517C>T	p.Arg173Cys	missense_variant	Exon 2 of 4	1		ENSP00000304440.1
HAS3	ENST00000219322.7	c.517C>T	p.Arg173Cys	missense_variant	Exon 2 of 4	1		ENSP00000219322.3
HAS3	ENST00000566118.5	c.517C>T	p.Arg173Cys	missense_variant	Exon 2 of 4	5		ENSP00000456246.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250864 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135766

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461704 Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8 AN XY: 727172

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.517C>T (p.R173C) 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 517, causing the arginine (R) at amino acid position 173 to be replaced by a cysteine (C). 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	0.13
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.0	L;L;.;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.17	T;T;T;T
Sift4G	Uncertain	0.059	T;T;T;T
Polyphen		0.97	D;D;.;D
Vest4		0.57
MutPred		0.54		Gain of catalytic residue at M171 (P = 0.0055);Gain of catalytic residue at M171 (P = 0.0055);Gain of catalytic residue at M171 (P = 0.0055);Gain of catalytic residue at M171 (P = 0.0055);
MVP		0.24
MPC		1.8
ClinPred		0.82	D
GERP RS		5.6
Varity_R		0.14
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

Other links and lift over

dbSNP: rs751988494; hg19: chr16-69143815; COSMIC: COSV54709002; COSMIC: COSV54709002;