chr11-6394652-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.11
Variant links:
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]

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ACMG classification

Classification made for transcript

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/exons MANE UniProt
SMPD1NM_000543.5 linkuse as main transcriptc.*45G>A 3_prime_UTR_variant 6/6 ENST00000342245.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SMPD1ENST00000342245.9 linkuse as main transcriptc.*45G>A 3_prime_UTR_variant 6/61 NM_000543.5 P3P17405-1

Frequencies

GnomAD3 genomes
AF:
0.166
AC:
25286
AN:
152168
Hom.:
2493
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Niemann-Pick disease, type A Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs8164; hg19: chr11-6415882; API