16-69109400-C-T

Variant names:

• chr16-69109400-C-T
• rs763308554
• NM_001199280.2:c.5C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001199280.2(HAS3):​c.5C>T​(p.Pro2Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000138 in 1,448,320 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: HAS3 NM_001199280.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAS3	NM_001199280.2	c.5C>T	p.Pro2Leu	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.5C>T	p.Pro2Leu	missense_variant	Exon 2 of 4	2	NM_001199280.2	ENSP00000454731.1
HAS3	ENST00000306560.1	c.5C>T	p.Pro2Leu	missense_variant	Exon 2 of 4	1		ENSP00000304440.1
HAS3	ENST00000219322.7	c.5C>T	p.Pro2Leu	missense_variant	Exon 2 of 4	1		ENSP00000219322.3
HAS3	ENST00000566118.5	c.5C>T	p.Pro2Leu	missense_variant	Exon 2 of 4	5		ENSP00000456246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000828 AC: 2 AN: 241672 Hom.: 0 AF XY: 0.00000764 AC XY: 1 AN XY: 130890

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: 0.0000338

Gnomad FIN exome AF: 0.0000571

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1448320 Hom.: 0 Cov.: 31 AF XY: 0.0000167 AC XY: 12 AN XY: 719682

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000704

Gnomad4 FIN exome AF: 0.0000209

Gnomad4 NFE exome AF: 0.00000903

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5C>T (p.P2L) 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 5, causing the proline (P) at amino acid position 2 to be replaced by a leucine (L). 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	0.19
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	.;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	2.0	M;M;.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.98	D;D;.;D
Vest4		0.65
MutPred		0.34		Loss of catalytic residue at P2 (P = 0.0049);Loss of catalytic residue at P2 (P = 0.0049);Loss of catalytic residue at P2 (P = 0.0049);Loss of catalytic residue at P2 (P = 0.0049);
MVP		0.19
MPC		1.6
ClinPred		0.73	D
GERP RS		5.4
Varity_R		0.49
gMVP		0.86

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: rs763308554; hg19: chr16-69143303; COSMIC: COSV54706873; COSMIC: COSV54706873;