rs144873307

Variant names:

• chr11-6394029-G-A
• rs144873307
• NM_000543.5:c.1474G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-6394029-G-A
• chr11-6394029-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_000543.5(SMPD1):​c.1474G>A​(p.Gly492Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G492R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16 B:1
• Conservation: PhyloP100: 0.00900
• Publications: 10 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 16 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=0.025081277).

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.1474G>A	p.Gly492Ser	missense	Exon 5 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.1471G>A	p.Gly491Ser	missense	Exon 5 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.1342G>A	p.Gly448Ser	missense	Exon 4 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.1474G>A	p.Gly492Ser	missense	Exon 5 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000526280.1	TSL:1	c.529G>A	p.Gly177Ser	missense	Exon 3 of 4	ENSP00000436278.1	H0YEP5
	SMPD1	ENST00000531303.5	TSL:1	n.*305G>A		non_coding_transcript_exon	Exon 5 of 6	ENSP00000432625.1	E9PPK6

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000935 AC: 235 AN: 251424 AF XY: 0.000979

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00184 AC: 2695 AN: 1461890 Hom.: 1 Cov.: 32 AF XY: 0.00179 AC XY: 1305 AN XY: 727248

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000893 AC: 77 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.00222 AC: 2467 AN: 1112012

Other (OTH) AF: 0.00141 AC: 85 AN: 60396

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74440

African (AFR) AF: 0.000578 AC: 24 AN: 41536

American (AMR) AF: 0.00105 AC: 16 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 68018

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.00102

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000955 AC: 116

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	4	-	Niemann-Pick disease, type A (4)
-	2	-	Niemann-Pick disease, type B (2)
-	2	-	Sphingomyelin/cholesterol lipidosis (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)
-	1	-	not specified (1)
-	1	-	SMPD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	7.3
DANN	Benign	0.80
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.89	T
PhyloP100		0.0090
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.25
Sift	Benign	0.42	T
Sift4G	Benign	0.50	T
Vest4		0.26
MVP		0.80
MPC		0.21
ClinPred		0.0013	T
GERP RS		-6.9
Varity_R		0.070
gMVP		0.51
Mutation Taster		=24/76	disease causing (ClinVar)

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: rs144873307; hg19: chr11-6415259;