rs74053349

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000543.5(SMPD1):c.559C>A(p.Pro187Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,482,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P187S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000092 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.759

Publications

8 publications found

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]

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)

SMPD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28102604).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMPD1	NM_000543.5	MANE Select	c.559C>A	p.Pro187Thr	missense	Exon 2 of 6	NP_000534.3
SMPD1	NM_001007593.3		c.556C>A	p.Pro186Thr	missense	Exon 2 of 6	NP_001007594.2	P17405-4
SMPD1	NM_001365135.2		c.559C>A	p.Pro187Thr	missense	Exon 2 of 5	NP_001352064.1	P17405-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.559C>A	p.Pro187Thr	missense	Exon 2 of 6	ENSP00000340409.4	P17405-1
SMPD1	ENST00000533123.5	TSL:1	n.559C>A		non_coding_transcript_exon	Exon 2 of 5	ENSP00000435950.1	G3V1E1
SMPD1	ENST00000534405.5	TSL:1	n.559C>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000434353.1	E9PQT3

Frequencies

GnomAD3 genomes

AF:

0.00000923

AC:

AN:

108378

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000194

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000285

AC:

AN:

140292

AF XY:

0.0000398

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000175

AC:

AN:

1373892

Hom.:

Cov.:

AF XY:

0.0000191

AC XY:

AN XY:

679304

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31242

American (AMR)

AF:

0.00

AC:

AN:

36164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25058

East Asian (EAS)

AF:

0.00

AC:

AN:

35822

South Asian (SAS)

AF:

0.000139

AC:

AN:

79004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45790

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4154

European-Non Finnish (NFE)

AF:

0.0000123

AC:

AN:

1059622

Other (OTH)

AF:

0.00

AC:

AN:

57036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000923

AC:

AN:

108378

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

51700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29756

American (AMR)

AF:

0.00

AC:

AN:

9288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2736

East Asian (EAS)

AF:

0.00

AC:

AN:

3654

South Asian (SAS)

AF:

0.00

AC:

AN:

3264

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.0000194

AC:

AN:

51440

Other (OTH)

AF:

0.00

AC:

AN:

1408

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000182

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

3.7

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.28

MetaSVM

Uncertain

0.57

PhyloP100

0.76

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.34

Sift

Benign

0.064

Sift4G

Benign

0.12

Vest4

0.22

MVP

0.97

MPC

0.35

ClinPred

0.55

GERP RS

-0.45

PromoterAI

0.030

Neutral

(source)

Varity_R

0.17

gMVP

0.78

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over