11-6391624-C-T

Position:

• chr11-6391624-C-T

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.559C>T​(p.Pro187Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,482,296 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (38 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (44 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.759

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]

SMPD1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031031668).
• BP6: Variant 11-6391624-C-T is Benign according to our data. Variant chr11-6391624-C-T is described in ClinVar as [Benign]. Clinvar id is 195087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.559C>T	p.Pro187Ser	missense_variant	2/6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.559C>T	p.Pro187Ser	missense_variant	2/6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 1875 AN: 108364 Hom.: 38 Cov.: 31

Gnomad AFR AF: 0.0581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00840

Gnomad ASJ AF: 0.00841

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00855

Gnomad NFE AF: 0.000447

Gnomad OTH AF: 0.0142

GnomAD3 exomes AF: 0.00453 AC: 635 AN: 140292 Hom.: 10 AF XY: 0.00352 AC XY: 265 AN XY: 75318

Gnomad AFR exome AF: 0.0594

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.00812

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000472

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000367

Gnomad OTH exome AF: 0.00378

GnomAD4 exome AF: 0.00164 AC: 2257 AN: 1373882 Hom.: 44 Cov.: 33 AF XY: 0.00149 AC XY: 1011 AN XY: 679298

Gnomad4 AFR exome AF: 0.0481

Gnomad4 AMR exome AF: 0.00288

Gnomad4 ASJ exome AF: 0.00690

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000633

Gnomad4 FIN exome AF: 0.0000218

Gnomad4 NFE exome AF: 0.000235

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.0173 AC: 1880 AN: 108414 Hom.: 38 Cov.: 31 AF XY: 0.0165 AC XY: 856 AN XY: 51746

Gnomad4 AFR AF: 0.0582

Gnomad4 AMR AF: 0.00838

Gnomad4 ASJ AF: 0.00841

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000447

Gnomad4 OTH AF: 0.0141

Alfa AF: 0.00116 Hom.: 1

ESP6500AA AF: 0.0448 AC: 196

ESP6500EA AF: 0.00129 AC: 11

ExAC AF: 0.00371 AC: 408

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 08, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2017	Variant summary: The SMPD1 c.559C>T (p.Pro187Ser) variant involves the alteration of a non-conserved nucleotide and 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant was found in 968/157662 (16 homozygotes) control chromosomes (gnomAD), predominantly observed in the African subpopulation at a frequency of 0.057086 (804/14084, 16 homozygotes)). This frequency is about 26 times the estimated maximal expected allele frequency of a pathogenic SMPD1 variant (0.0022361), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor was it evaluated for functional impact by in vivo/vitro studies. However, multiple clinical diagnostic laboratories/reputable databases classified this variant as "benign". Taken together, this variant is classified as Benign. -

Niemann-Pick disease, type A Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 14, 2017	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	4.9
DANN	Benign	0.95
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Uncertain	-0.26	T
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Benign	0.21
Sift	Benign	0.077	T;T
Sift4G	Benign	0.17	T;T
Vest4		0.15
MVP		0.97
MPC		0.28
ClinPred		0.017	T
GERP RS		-0.45
Varity_R		0.12
gMVP		0.75

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: rs74053349; hg19: chr11-6412854;