NM_033159.4:c.*434C>T

Variant names:

• chr3-50300049-G-A
• rs182987423
• NM_033159.4:c.*434C>T

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.*434C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000497 in 253,462 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 0.00075 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: HYAL1 NM_033159.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.810
• 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

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 afr. GnomAd4 allele frequency = 0.000749 (114/152294) while in subpopulation AFR AF = 0.00253 (105/41556). AF 95% confidence interval is 0.00213. There are 0 homozygotes in GnomAd4. There are 59 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.*434C>T		3_prime_UTR	Exon 4 of 4	NP_149349.2
	HYAL1	NM_153281.2		c.*434C>T		3_prime_UTR	Exon 6 of 6	NP_695013.1	Q12794-1
	HYAL1	NM_153282.3		c.*434C>T		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.*434C>T		3_prime_UTR	Exon 4 of 4	ENSP00000378576.2	Q12794-1
	HYAL1	ENST00000266031.8	TSL:1	c.*434C>T		3_prime_UTR	Exon 3 of 3	ENSP00000266031.4	Q12794-1
	HYAL1	ENST00000320295.12	TSL:2	c.*434C>T		3_prime_UTR	Exon 6 of 6	ENSP00000346068.5	Q12794-1

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000119 AC: 12 AN: 101168 Hom.: 0 Cov.: 0 AF XY: 0.000128 AC XY: 7 AN XY: 54684

African (AFR) AF: 0.00136 AC: 5 AN: 3666

American (AMR) AF: 0.00 AC: 0 AN: 5272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2418

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.000396 AC: 7 AN: 17676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 382

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59226

Other (OTH) AF: 0.00 AC: 0 AN: 4920

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000792 AC XY: 59 AN XY: 74450

African (AFR) AF: 0.00253 AC: 105 AN: 41556

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000693 Hom.: 0

Bravo AF: 0.000801

ClinVar

ClinVar submissions as Germline

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	12
DANN	Benign	0.70
PhyloP100		0.81

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: rs182987423; hg19: chr3-50337480;