NM_000543.5:c.559C>T

Variant names:

• chr11-6391624-C-T
• rs74053349
• NM_000543.5:c.559C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P187T) has been classified as Uncertain significance.

• 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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• acid sphingomyelinase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Niemann-Pick disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Niemann-Pick disease type A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia, G2P
• Niemann-Pick disease type B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000543.5
• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000543.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD1	NM_000543.5	MANE Select	c.559C>T	p.Pro187Ser	missense	Exon 2 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.556C>T	p.Pro186Ser	missense	Exon 2 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.559C>T	p.Pro187Ser	missense	Exon 2 of 5	NP_001352064.1	P17405-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.559C>T	p.Pro187Ser	missense	Exon 2 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000533123.5	TSL:1	n.559C>T		non_coding_transcript_exon	Exon 2 of 5	ENSP00000435950.1	G3V1E1
	SMPD1	ENST00000534405.5	TSL:1	n.559C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000434353.1	E9PQT3

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

GnomAD2 exomes AF: 0.00453 AC: 635 AN: 140292 AF XY: 0.00352

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 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

African (AFR) AF: 0.0481 AC: 1501 AN: 31230

American (AMR) AF: 0.00288 AC: 104 AN: 36164

Ashkenazi Jewish (ASJ) AF: 0.00690 AC: 173 AN: 25058

East Asian (EAS) AF: 0.00 AC: 0 AN: 35822

South Asian (SAS) AF: 0.0000633 AC: 5 AN: 79004

European-Finnish (FIN) AF: 0.0000218 AC: 1 AN: 45790

Middle Eastern (MID) AF: 0.00120 AC: 5 AN: 4154

European-Non Finnish (NFE) AF: 0.000235 AC: 249 AN: 1059624

Other (OTH) AF: 0.00384 AC: 219 AN: 57036

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

African (AFR) AF: 0.0582 AC: 1734 AN: 29794

American (AMR) AF: 0.00838 AC: 78 AN: 9310

Ashkenazi Jewish (ASJ) AF: 0.00841 AC: 23 AN: 2736

East Asian (EAS) AF: 0.00 AC: 0 AN: 3652

South Asian (SAS) AF: 0.00 AC: 0 AN: 3266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5946

Middle Eastern (MID) AF: 0.00952 AC: 2 AN: 210

European-Non Finnish (NFE) AF: 0.000447 AC: 23 AN: 51428

Other (OTH) AF: 0.0141 AC: 20 AN: 1420

Alfa AF: 0.00451 Hom.: 8

ESP6500AA AF: 0.0448 AC: 196

ESP6500EA AF: 0.00129 AC: 11

ExAC AF: 0.00371 AC: 408

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Niemann-Pick disease, type A (2)
-	-	2	not specified (2)
-	-	1	Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0031	T
MetaSVM	Uncertain	-0.26	T
PhyloP100		0.76
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.21
Sift	Benign	0.077	T
Sift4G	Benign	0.17	T
Vest4		0.15
MVP		0.97
MPC		0.28
ClinPred		0.017	T
GERP RS		-0.45
PromoterAI		0.025	Neutral
Varity_R		0.12
gMVP		0.75
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs74053349; hg19: chr11-6412854;