chr6-31862690-C-T

Variant names:

• chr6-31862690-C-T
• rs104893984
• NM_000434.4:c.87G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000434.4(NEU1):​c.87G>A​(p.Trp29*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEU1 NM_000434.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.859
• Publications: 3 publications found

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: G2P, Genomics England PanelApp, 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 55 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-31862690-C-T is Pathogenic according to our data. Variant chr6-31862690-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2451.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEU1	NM_000434.4	MANE Select	c.87G>A	p.Trp29*	stop_gained	Exon 1 of 6	NP_000425.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEU1	ENST00000375631.5	TSL:1 MANE Select	c.87G>A	p.Trp29*	stop_gained	Exon 1 of 6	ENSP00000364782.4
	NEU1	ENST00000850553.1		c.87G>A	p.Trp29*	stop_gained	Exon 1 of 6	ENSP00000520846.1
	NEU1	ENST00000480384.1	TSL:2	n.116G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000800 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Sialidosis type 2 Pathogenic:1

Oct 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Apr 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2451). This premature translational stop signal has been observed in individual(s) with clinical features of sialidosis type II (PMID: 11702224). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp29*) in the NEU1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEU1 are known to be pathogenic (PMID: 11063730, 14517945).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	33
DANN	Uncertain	0.98
Eigen	Benign	0.13
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		0.86
Vest4		0.38
GERP RS		3.6
PromoterAI		-0.059	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Mutation Taster		=6/194	disease causing (ClinVar)

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: rs104893984; hg19: chr6-31830467;