6-31859793-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000434.4(NEU1):c.1174C>G(p.Leu392Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L392L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NEU1 NM_000434.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.475

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37841144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEU1	NM_000434.4	c.1174C>G	p.Leu392Val	missense_variant	6/6	ENST00000375631.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEU1	ENST00000375631.5	c.1174C>G	p.Leu392Val	missense_variant	6/6	1	NM_000434.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246594 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134416

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460760 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726700

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

NEU1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 2023

The NEU1 c.1174C>G variant is predicted to result in the amino acid substitution p.Leu392Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.74	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.70	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.18
Sift	Benign	0.15	T
Sift4G	Benign	0.16	T
Polyphen		0.30	B
Vest4		0.30
MutPred		0.57		Gain of methylation at K395 (P = 0.0688);
MVP		0.91
MPC		0.60
ClinPred		0.12	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.53

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: rs1286901072; hg19: chr6-31827570;