Genetic Variant HYAL1:p.Ala426Glu (chr3-50300514-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_033159.4(HYAL1):c.1277C>A(p.Ala426Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A426G) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Consequence

HYAL1
NM_033159.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.57

Publications

0 publications found

Variant links:

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

HYAL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38238072).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HYAL1	NM_033159.4	MANE Select	c.1277C>A	p.Ala426Glu	missense	Exon 4 of 4	NP_149349.2
HYAL1	NM_153281.2		c.1277C>A	p.Ala426Glu	missense	Exon 6 of 6	NP_695013.1	Q12794-1
HYAL1	NM_153282.3		c.1187C>A	p.Ala396Glu	missense	Exon 3 of 3	NP_695014.1	Q12794-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HYAL1	ENST00000395144.7	TSL:1 MANE Select	c.1277C>A	p.Ala426Glu	missense	Exon 4 of 4	ENSP00000378576.2	Q12794-1
HYAL1	ENST00000266031.8	TSL:1	c.1277C>A	p.Ala426Glu	missense	Exon 3 of 3	ENSP00000266031.4	Q12794-1
HYAL1	ENST00000395143.6	TSL:1	c.1187C>A	p.Ala396Glu	missense	Exon 3 of 3	ENSP00000378575.2	Q12794-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.39

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.51

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.61

M_CAP

Benign

0.023

MetaRNN

Benign

0.38

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

3.6

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.0

REVEL

Benign

0.23

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.067

Vest4

0.29

MutPred

0.72

Gain of solvent accessibility (P = 0.0016)

MVP

0.29

MPC

0.24

ClinPred

0.65

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.98

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over