rs1050239

Variant names:

• chr11-6394233-G-A
• rs1050239
• NM_000543.5:c.1522G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-6394233-G-A
• chr11-6394233-G-C
• chr11-6394233-G-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.1522G>A​(p.Gly508Arg) variant causes a missense change. The variant allele was found at a frequency of 0.219 in 1,613,854 control chromosomes in the GnomAD database, including 40,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G508G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (2946 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37073 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 6.33
• Publications: 68 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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000543.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019872487).
• BP6: Variant 11-6394233-G-A is Benign according to our data. Variant chr11-6394233-G-A is described in ClinVar as Benign. ClinVar VariationId is 93317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 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.1522G>A	p.Gly508Arg	missense	Exon 6 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.1519G>A	p.Gly507Arg	missense	Exon 6 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.1390G>A	p.Gly464Arg	missense	Exon 5 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.1522G>A	p.Gly508Arg	missense	Exon 6 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000526280.1	TSL:1	c.577G>A	p.Gly193Arg	missense	Exon 4 of 4	ENSP00000436278.1	H0YEP5
	SMPD1	ENST00000531303.5	TSL:1	n.*373G>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000432625.1	E9PPK6

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29236 AN: 151956 Hom.: 2942 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.191 AC: 48098 AN: 251326 AF XY: 0.190

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.137

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.221 AC: 323546 AN: 1461780 Hom.: 37073 Cov.: 37 AF XY: 0.219 AC XY: 158913 AN XY: 727214

African (AFR) AF: 0.133 AC: 4460 AN: 33476

American (AMR) AF: 0.167 AC: 7466 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4557 AN: 26136

East Asian (EAS) AF: 0.139 AC: 5507 AN: 39696

South Asian (SAS) AF: 0.129 AC: 11138 AN: 86250

European-Finnish (FIN) AF: 0.216 AC: 11537 AN: 53412

Middle Eastern (MID) AF: 0.144 AC: 828 AN: 5768

European-Non Finnish (NFE) AF: 0.239 AC: 265705 AN: 1111928

Other (OTH) AF: 0.204 AC: 12348 AN: 60392

GnomAD4 genome AF: 0.192 AC: 29255 AN: 152074 Hom.: 2946 Cov.: 32 AF XY: 0.189 AC XY: 14052 AN XY: 74342

African (AFR) AF: 0.139 AC: 5761 AN: 41484

American (AMR) AF: 0.174 AC: 2659 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 624 AN: 3472

East Asian (EAS) AF: 0.146 AC: 753 AN: 5162

South Asian (SAS) AF: 0.121 AC: 583 AN: 4818

European-Finnish (FIN) AF: 0.216 AC: 2289 AN: 10574

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15870 AN: 67966

Other (OTH) AF: 0.189 AC: 398 AN: 2110

Alfa AF: 0.215 Hom.: 15169

Bravo AF: 0.187

TwinsUK AF: 0.243 AC: 901

ALSPAC AF: 0.241 AC: 930

ESP6500AA AF: 0.137 AC: 604

ESP6500EA AF: 0.229 AC: 1970

ExAC AF: 0.192 AC: 23270

EpiCase AF: 0.224

EpiControl AF: 0.222

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	3	Niemann-Pick disease, type A (3)
-	-	1	Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)
-	-	1	Niemann-Pick disease, type B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
PhyloP100		6.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.50
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Vest4		0.15
MPC		0.47
ClinPred		0.038	T
GERP RS		3.8
Varity_R		0.094
gMVP		0.77
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1050239; hg19: chr11-6415463; COSMIC: COSV54967048; COSMIC: COSV54967048;