3-50303895-C-T

Position:

• chr3-50303895-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153281.2(HYAL1):​c.-132G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.054 in 152,224 control chromosomes in the GnomAD database, including 1,552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (1552 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HYAL1 NM_153281.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.895

Genes affected

HYAL1 (HGNC:5320): (hyaluronidase 1) This gene encodes a lysosomal hyaluronidase. Hyaluronidases intracellularly degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan is thought to be involved in cell proliferation, migration and differentiation. This enzyme is active at an acidic pH and is the major hyaluronidase in plasma. Mutations in this gene are associated with mucopolysaccharidosis type IX, or hyaluronidase deficiency. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-50303895-C-T is Benign according to our data. Variant chr3-50303895-C-T is described in ClinVar as [Benign]. Clinvar id is 346093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYAL1	NM_153281.2	c.-132G>A		5_prime_UTR_premature_start_codon_gain_variant	3/6		NP_695013.1
HYAL1	XM_011533668.3	c.-132G>A		5_prime_UTR_premature_start_codon_gain_variant	1/4		XP_011531970.1
HYAL1	NM_153281.2	c.-132G>A		5_prime_UTR_variant	3/6		NP_695013.1
HYAL1	XM_011533668.3	c.-132G>A		5_prime_UTR_variant	1/4		XP_011531970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HYAL1	ENST00000320295.12	c.-132G>A		5_prime_UTR_premature_start_codon_gain_variant	3/6	2		ENSP00000346068.5
HYAL1	ENST00000618175.4	c.-132G>A		5_prime_UTR_premature_start_codon_gain_variant	1/4	5		ENSP00000477903.1
HYAL1	ENST00000452672.1	c.-132G>A		5_prime_UTR_premature_start_codon_gain_variant	1/2	4		ENSP00000391666.1

Frequencies

GnomAD3 genomes AF: 0.0540 AC: 8211 AN: 152106 Hom.: 1551 Cov.: 32

Gnomad AFR AF: 0.00804

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.600

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00349

Gnomad OTH AF: 0.0564

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 18 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 16

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0540 AC: 8218 AN: 152224 Hom.: 1552 Cov.: 32 AF XY: 0.0623 AC XY: 4635 AN XY: 74420

Gnomad4 AFR AF: 0.00801

Gnomad4 AMR AF: 0.247

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.600

Gnomad4 SAS AF: 0.0188

Gnomad4 FIN AF: 0.0511

Gnomad4 NFE AF: 0.00349

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0217 Hom.: 409

Bravo AF: 0.0719

Asia WGS AF: 0.197 AC: 681 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of hyaluronoglucosaminidase Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.3
DANN	Benign	0.91

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12488302; hg19: chr3-50341326;