chr3-50300024-C-T

Variant names:

• chr3-50300024-C-T
• rs150976767
• NM_033159.4:c.*459G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_033159.4(HYAL1):​c.*459G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 243,340 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: HYAL1 NM_033159.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.341
• Publications: 0 publications found

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]

HYAL1 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 9

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp, Ambry Genetics, Orphanet

ENSG00000295204 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000217 (33/152354) while in subpopulation AMR AF = 0.000457 (7/15302). AF 95% confidence interval is 0.000215. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033159.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYAL1	NM_033159.4	MANE Select	c.*459G>A		3_prime_UTR	Exon 4 of 4	NP_149349.2
	HYAL1	NM_153281.2		c.*459G>A		3_prime_UTR	Exon 6 of 6	NP_695013.1	Q12794-1
	HYAL1	NM_153282.3		c.*459G>A		3_prime_UTR	Exon 3 of 3	NP_695014.1	Q12794-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYAL1	ENST00000395144.7	TSL:1 MANE Select	c.*459G>A		3_prime_UTR	Exon 4 of 4	ENSP00000378576.2	Q12794-1
	HYAL1	ENST00000266031.8	TSL:1	c.*459G>A		3_prime_UTR	Exon 3 of 3	ENSP00000266031.4	Q12794-1
	HYAL1	ENST00000320295.12	TSL:2	c.*459G>A		3_prime_UTR	Exon 6 of 6	ENSP00000346068.5	Q12794-1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00605

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

GnomAD4 exome AF: 0.000154 AC: 14 AN: 90986 Hom.: 0 Cov.: 0 AF XY: 0.000163 AC XY: 8 AN XY: 49048

African (AFR) AF: 0.00 AC: 0 AN: 3286

American (AMR) AF: 0.000208 AC: 1 AN: 4810

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 6 AN: 2094

East Asian (EAS) AF: 0.00 AC: 0 AN: 4772

South Asian (SAS) AF: 0.00 AC: 0 AN: 15696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53392

Other (OTH) AF: 0.00114 AC: 5 AN: 4392

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74488

African (AFR) AF: 0.0000481 AC: 2 AN: 41572

American (AMR) AF: 0.000457 AC: 7 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000287

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Deficiency of hyaluronoglucosaminidase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.4
DANN	Benign	0.74
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs150976767; hg19: chr3-50337455;