6-31859509-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000434.4(NEU1):c.*210T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0417 in 657,548 control chromosomes in the GnomAD database, including 813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (279 hom., cov: 32)
  • Exomes 𝑓: 0.039 (534 hom.)
• Consequence: NEU1 NM_000434.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.112

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-31859509-A-T is Benign according to our data. Variant chr6-31859509-A-T is described in ClinVar as [Benign]. Clinvar id is 356229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEU1	NM_000434.4	c.*210T>A		3_prime_UTR_variant	6/6	ENST00000375631.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEU1	ENST00000375631.5	c.*210T>A		3_prime_UTR_variant	6/6	1	NM_000434.4	P1

Frequencies

GnomAD3 genomes AF: 0.0521 AC: 7935 AN: 152170 Hom.: 278 Cov.: 32

Gnomad AFR AF: 0.0999

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0740

Gnomad EAS AF: 0.0375

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.0344

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0329

Gnomad OTH AF: 0.0540

GnomAD4 exome AF: 0.0385 AC: 19456 AN: 505260 Hom.: 534 Cov.: 4 AF XY: 0.0379 AC XY: 10239 AN XY: 270388

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.0305

Gnomad4 ASJ exome AF: 0.0825

Gnomad4 EAS exome AF: 0.0588

Gnomad4 SAS exome AF: 0.0277

Gnomad4 FIN exome AF: 0.0322

Gnomad4 NFE exome AF: 0.0339

Gnomad4 OTH exome AF: 0.0404

GnomAD4 genome AF: 0.0522 AC: 7944 AN: 152288 Hom.: 279 Cov.: 32 AF XY: 0.0523 AC XY: 3892 AN XY: 74468

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.0303

Gnomad4 ASJ AF: 0.0740

Gnomad4 EAS AF: 0.0376

Gnomad4 SAS AF: 0.0271

Gnomad4 FIN AF: 0.0344

Gnomad4 NFE AF: 0.0329

Gnomad4 OTH AF: 0.0534

Alfa AF: 0.0412 Hom.: 91

Bravo AF: 0.0555

Asia WGS AF: 0.0310 AC: 107 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sialidosis type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	3.5
Dann	Benign	0.62

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: rs13118; hg19: chr6-31827286;