rs8164

Variant names:

• chr11-6394652-G-A
• rs8164
• NM_000543.5:c.*45G>A

Variant summary

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

The NM_000543.5(SMPD1):​c.*45G>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 0.142 in 1,531,524 control chromosomes in the GnomAD database, including 16,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2501 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14454 hom.)
• Consequence: SMPD1 NM_000543.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.11

Genes affected

SMPD1 (HGNC:11120): (sphingomyelin phosphodiesterase 1) The protein encoded by this gene is a lysosomal acid sphingomyelinase that converts sphingomyelin to ceramide. The encoded protein also has phospholipase C activity. Defects in this gene are a cause of Niemann-Pick disease type A (NPA) and Niemann-Pick disease type B (NPB). Multiple transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-6394652-G-A is Benign according to our data. Variant chr11-6394652-G-A is described in ClinVar as [Benign]. Clinvar id is 305208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.*45G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.*45G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25286 AN: 152168 Hom.: 2493 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0985

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.131 AC: 28896 AN: 220964 Hom.: 2263 AF XY: 0.133 AC XY: 16270 AN XY: 122172

Gnomad AFR exome AF: 0.283

Gnomad AMR exome AF: 0.0798

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.00402

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.139 AC: 191808 AN: 1379238 Hom.: 14454 Cov.: 22 AF XY: 0.140 AC XY: 96671 AN XY: 689874

Gnomad4 AFR exome AF: 0.278

Gnomad4 AMR exome AF: 0.0848

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.00313

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.166 AC: 25320 AN: 152286 Hom.: 2501 Cov.: 33 AF XY: 0.163 AC XY: 12174 AN XY: 74468

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.0985

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.161

Alfa AF: 0.145 Hom.: 2297

Bravo AF: 0.172

Asia WGS AF: 0.0850 AC: 294 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Niemann-Pick disease, type A Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.12
DANN	Benign	0.61

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: rs8164; hg19: chr11-6415882;