NM_000434.4:c.674G>C

Variant names:

• chr6-31860563-C-G
• rs104893980
• NM_000434.4:c.674G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000434.4(NEU1):​c.674G>C​(p.Arg225Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEU1 NM_000434.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.19

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 6-31860563-C-G is Pathogenic according to our data. Variant chr6-31860563-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2456.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-31860563-C-G is described in UniProt as null. Variant chr6-31860563-C-G is described in UniProt as null. Variant chr6-31860563-C-G is described in UniProt as null. Variant chr6-31860563-C-G is described in UniProt as null. Variant chr6-31860563-C-G is described in UniProt as null. Variant chr6-31860563-C-G is described in UniProt as null. Variant chr6-31860563-C-G is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEU1	NM_000434.4	c.674G>C	p.Arg225Pro	missense_variant	Exon 4 of 6	ENST00000375631.5	NP_000425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEU1	ENST00000375631.5	c.674G>C	p.Arg225Pro	missense_variant	Exon 4 of 6	1	NM_000434.4	ENSP00000364782.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Sialidosis type 2 Pathogenic:1

Jan 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.46	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.62
Sift	Benign	0.27	T
Sift4G	Benign	0.28	T
Polyphen		0.80	P
Vest4		0.75
MutPred		0.82		Loss of sheet (P = 0.0817);
MVP		0.97
MPC		1.6
ClinPred		0.79	D
GERP RS		3.3
Varity_R		0.22
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs104893980; hg19: chr6-31828340;