Genetic Variant NEU1:p.Ala298Val (chr6-31860170-G-A) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_000434.4(NEU1):c.893C>T(p.Ala298Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,612,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000461928: Functional studies using COS-7 cells and sialidosis-deficient human fibroblasts demonstrated that the p.Ala298Val variant has very low sialidase activity compared to wild type NEU1, and the p.Ala298Val variant also results in aberrant localization of the NEU1 protein, likely due to protein misfolding (Lukong et al. 2000" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

NEU1
NM_000434.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.94

Publications

12 publications found

Variant links:

Genes affected

NEU1 (HGNC:7758): (neuraminidase 1) The protein encoded by this gene is a lysosomal enzyme that cleaves terminal sialic acid residues from substrates such as glycoproteins and glycolipids. In the lysosome, this enzyme is part of a heterotrimeric complex together with beta-galactosidase and cathepsin A (the latter is also referred to as 'protective protein'). Mutations in this gene can lead to sialidosis, a lysosomal storage disease that can be type 1 (cherry red spot-myoclonus syndrome or normosomatic type), which is late-onset, or type 2 (the dysmorphic type), which occurs at an earlier age with increased severity. [provided by RefSeq, Jul 2008]

NEU1 Gene-Disease associations (from GenCC):

sialidosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
sialidosis type 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
congenital sialidosis type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
juvenile sialidosis type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sialidosis type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NEU1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000461928: Functional studies using COS-7 cells and sialidosis-deficient human fibroblasts demonstrated that the p.Ala298Val variant has very low sialidase activity compared to wild type NEU1, and the p.Ala298Val variant also results in aberrant localization of the NEU1 protein, likely due to protein misfolding (Lukong et al. 2000; Pattison et al. 2004).; SCV001505483: Experimental studies have shown that this missense change affects NEU1 function (PMID: 10767332, 11279074, 14695530).; SCV004028701: Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in <10% enzymatic activity, which is likely due to protein misfolding (e.g, Lukong_2000, Lukong_2001, Pattison_2004). PMID: 10767332, 11279074, 14695530

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 4 uncertain in NM_000434.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 1.4218 (below the threshold of 3.09). Trascript score misZ: 2.2638 (below the threshold of 3.09). GenCC associations: The gene is linked to juvenile sialidosis type 2, sialidosis type 1, sialidosis, sialidosis type 2, congenital sialidosis type 2.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

PP5

Variant 6-31860170-G-A is Pathogenic according to our data. Variant chr6-31860170-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000434.4. 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
	NEU1	NM_000434.4	MANE Select	c.893C>T	p.Ala298Val	missense	Exon 5 of 6	NP_000425.1	Q5JQI0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEU1	ENST00000375631.5	TSL:1 MANE Select	c.893C>T	p.Ala298Val	missense	Exon 5 of 6	ENSP00000364782.4	Q99519
NEU1	ENST00000850553.1		c.887C>T	p.Ala296Val	missense	Exon 5 of 6	ENSP00000520846.1	A0ABB0MVI7
NEU1	ENST00000877813.1		c.845C>T	p.Ala282Val	missense	Exon 5 of 6	ENSP00000547872.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000406

AC:

AN:

246526

AF XY:

0.0000447

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000601

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000271

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1460770

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726696

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000995

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1112004

Other (OTH)

AF:

0.0000994

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000468

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000333

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Sialidosis type 2 (2)

not provided (1)

Sialidosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.76

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.93

MetaSVM

Benign

-0.32

MutationAssessor

Uncertain

2.2

PhyloP100

1.9

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.63

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

0.79

Vest4

0.79

MutPred

0.85

Loss of sheet (P = 0.1907)

MVP

0.93

MPC

1.3

ClinPred

0.49

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.76

Mutation Taster

=91/9

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over