3-50318299-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003773.5(HYAL2):c.1252A>C(p.Ile418Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0433 in 1,613,504 control chromosomes in the GnomAD database, including 13,055 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.10 (2295 hom., cov: 32)
  • Exomes 𝑓: 0.037 (10760 hom.)
• Consequence: HYAL2 NM_003773.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.344

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2889481E-5).
• BP6: Variant 3-50318299-T-G is Benign according to our data. Variant chr3-50318299-T-G is described in ClinVar as [Benign]. Clinvar id is 1229880.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HYAL2	NM_003773.5	c.1252A>C	p.Ile418Leu	missense_variant	4/4	ENST00000357750.9
HYAL2	NM_033158.5	c.1252A>C	p.Ile418Leu	missense_variant	5/5
HYAL2	XM_005265524.3	c.1252A>C	p.Ile418Leu	missense_variant	5/5
HYAL2	XM_005265525.3	c.1252A>C	p.Ile418Leu	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYAL2	ENST00000357750.9	c.1252A>C	p.Ile418Leu	missense_variant	4/4	1	NM_003773.5	P1
HYAL2	ENST00000395139.7	c.1252A>C	p.Ile418Leu	missense_variant	4/4	1		P1
HYAL2	ENST00000447092.5	c.1252A>C	p.Ile418Leu	missense_variant	3/3	1		P1
HYAL2	ENST00000442581.1	c.1252A>C	p.Ile418Leu	missense_variant	5/5	2		P1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15854 AN: 152196 Hom.: 2293 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0468

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00362

Gnomad OTH AF: 0.0876

GnomAD3 exomes AF: 0.121 AC: 30469 AN: 250792 Hom.: 7048 AF XY: 0.0988 AC XY: 13414 AN XY: 135746

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.411

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.613

Gnomad SAS exome AF: 0.00892

Gnomad FIN exome AF: 0.0446

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.0677

GnomAD4 exome AF: 0.0369 AC: 53907 AN: 1461190 Hom.: 10760 Cov.: 31 AF XY: 0.0334 AC XY: 24282 AN XY: 726914

Gnomad4 AFR exome AF: 0.196

Gnomad4 AMR exome AF: 0.389

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.535

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.0441

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.0568

GnomAD4 genome AF: 0.104 AC: 15882 AN: 152314 Hom.: 2295 Cov.: 32 AF XY: 0.111 AC XY: 8253 AN XY: 74482

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.267

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.599

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.0468

Gnomad4 NFE AF: 0.00362

Gnomad4 OTH AF: 0.0881

Alfa AF: 0.0416 Hom.: 1131

Bravo AF: 0.130

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.174 AC: 768

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.107 AC: 12961

Asia WGS AF: 0.204 AC: 709 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	15
Dann	Benign	0.66
DEOGEN2	Benign	0.21	T;T;T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.36	N
MetaRNN	Benign	0.000013	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.1	N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.090	N;N;N;N
REVEL	Benign	0.096
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.87	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.034
MPC		0.50
ClinPred		0.0018	T
GERP RS		5.2
Varity_R		0.062
gMVP		0.52

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: rs35455589; hg19: chr3-50355730; COSMIC: COSV63306748; COSMIC: COSV63306748;