6-31859274-A-C

Position:

• chr6-31859274-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000434.4(NEU1):​c.*445T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 322,942 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: NEU1 NM_000434.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.245

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-31859274-A-C is Benign according to our data. Variant chr6-31859274-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 356227.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00176 (268/152362) while in subpopulation AMR AF= 0.00327 (50/15300). AF 95% confidence interval is 0.00255. There are 0 homozygotes in gnomad4. There are 114 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEU1	NM_000434.4	c.*445T>G		3_prime_UTR_variant	6/6	ENST00000375631.5	NP_000425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEU1	ENST00000375631.5	c.*445T>G		3_prime_UTR_variant	6/6	1	NM_000434.4	ENSP00000364782	P1

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 263 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00551

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00183 AC: 313 AN: 170580 Hom.: 2 Cov.: 0 AF XY: 0.00183 AC XY: 166 AN XY: 90482

Gnomad4 AFR exome AF: 0.00225

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.000115

Gnomad4 SAS exome AF: 0.000335

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00244

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152362 Hom.: 0 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74516

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00235

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.00217

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sialidosis type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.94
DANN	Benign	0.66

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: rs113824527; hg19: chr6-31827051;