3-50318387-A-G

Variant names:

• chr3-50318387-A-G
• rs150004751
• NM_003773.5:c.1164T>C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6 BP7 BS1

The NM_003773.5(HYAL2):​c.1164T>C​(p.His388His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,613,368 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 Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: HYAL2 NM_003773.5 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.55

Genes affected

HYAL2 (HGNC:5321): (hyaluronidase 2) This gene encodes a weak acid-active hyaluronidase. The encoded protein is similar in structure to other more active hyaluronidases. Hyaluronidases degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan and fragments of hyaluronan are thought to be involved in cell proliferation, migration and differentiation. Although it was previously thought to be a lysosomal hyaluronidase that is active at a pH below 4, the encoded protein is likely a GPI-anchored cell surface protein. This hyaluronidase serves as a receptor for the oncogenic virus Jaagsiekte sheep retrovirus. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. This gene encodes two alternatively spliced transcript variants which differ only in the 5' UTR.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 3-50318387-A-G is Benign according to our data. Variant chr3-50318387-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3052597.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.55 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00161 (246/152394) while in subpopulation AFR AF= 0.0057 (237/41598). AF 95% confidence interval is 0.0051. There are 0 homozygotes in gnomad4. There are 112 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYAL2	NM_003773.5	c.1164T>C	p.His388His	synonymous_variant	Exon 4 of 4	ENST00000357750.9	NP_003764.3
HYAL2	NM_033158.5	c.1164T>C	p.His388His	synonymous_variant	Exon 5 of 5		NP_149348.2
HYAL2	XM_005265524.3	c.1164T>C	p.His388His	synonymous_variant	Exon 5 of 5		XP_005265581.1
HYAL2	XM_005265525.3	c.1164T>C	p.His388His	synonymous_variant	Exon 4 of 4		XP_005265582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HYAL2	ENST00000357750.9	c.1164T>C	p.His388His	synonymous_variant	Exon 4 of 4	1	NM_003773.5	ENSP00000350387.4
HYAL2	ENST00000395139.7	c.1164T>C	p.His388His	synonymous_variant	Exon 4 of 4	1		ENSP00000378571.3
HYAL2	ENST00000447092.5	c.1164T>C	p.His388His	synonymous_variant	Exon 3 of 3	1		ENSP00000401853.1
HYAL2	ENST00000442581.1	c.1164T>C	p.His388His	synonymous_variant	Exon 5 of 5	2		ENSP00000406657.1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152276 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00571

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000411 AC: 103 AN: 250778 Hom.: 0 AF XY: 0.000346 AC XY: 47 AN XY: 135810

Gnomad AFR exome AF: 0.00575

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000153 AC: 224 AN: 1460974 Hom.: 0 Cov.: 31 AF XY: 0.000142 AC XY: 103 AN XY: 726796

Gnomad4 AFR exome AF: 0.00496

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00161 AC: 246 AN: 152394 Hom.: 0 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74530

Gnomad4 AFR AF: 0.00570

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.00210

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HYAL2-related disorder Benign:1

Apr 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.2
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs150004751; hg19: chr3-50355818;