chr3-50300377-C-G

Variant names:

• chr3-50300377-C-G
• rs903056291
• NM_033159.4:c.*106G>C

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.*106G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 1,152,836 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 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: HYAL1 NM_033159.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.403
• 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

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 sas. GnomAdExome4 allele frequency = 0.000072 (72/1000650) while in subpopulation SAS AF = 0.000917 (69/75242). AF 95% confidence interval is 0.000743. There are 0 homozygotes in GnomAdExome4. There are 61 alleles in the male GnomAdExome4 subpopulation. Median coverage is 13. 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.*106G>C		3_prime_UTR	Exon 4 of 4	NP_149349.2
	HYAL1	NM_153281.2		c.*106G>C		3_prime_UTR	Exon 6 of 6	NP_695013.1	Q12794-1
	HYAL1	NM_153282.3		c.*106G>C		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.*106G>C		3_prime_UTR	Exon 4 of 4	ENSP00000378576.2	Q12794-1
	HYAL1	ENST00000266031.8	TSL:1	c.*106G>C		3_prime_UTR	Exon 3 of 3	ENSP00000266031.4	Q12794-1
	HYAL1	ENST00000395143.6	TSL:1	c.*106G>C		3_prime_UTR	Exon 3 of 3	ENSP00000378575.2	Q12794-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000720 AC: 72 AN: 1000650 Hom.: 0 Cov.: 13 AF XY: 0.000118 AC XY: 61 AN XY: 515668

African (AFR) AF: 0.00 AC: 0 AN: 24620

American (AMR) AF: 0.00 AC: 0 AN: 41982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22920

East Asian (EAS) AF: 0.00 AC: 0 AN: 37452

South Asian (SAS) AF: 0.000917 AC: 69 AN: 75242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3588

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 699210

Other (OTH) AF: 0.0000665 AC: 3 AN: 45132

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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	4.0
DANN	Benign	0.70
PhyloP100		-0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs903056291; hg19: chr3-50337808;