rs1057517195

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001318088.2(SMPD1):c.-405C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,558,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

SMPD1
NM_001318088.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.24

Publications

6 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: Genomics England PanelApp, Orphanet, G2P
Niemann-Pick disease type B
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: 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: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 11-6391622-C-T is Pathogenic according to our data. Variant chr11-6391622-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 371341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318088.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMPD1	NM_000543.5	MANE Select	c.557C>T	p.Pro186Leu	missense	Exon 2 of 6	NP_000534.3
SMPD1	NM_001318088.2		c.-405C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_001305017.1
SMPD1	NM_001007593.3		c.554C>T	p.Pro185Leu	missense	Exon 2 of 6	NP_001007594.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.557C>T	p.Pro186Leu	missense	Exon 2 of 6	ENSP00000340409.4
SMPD1	ENST00000533123.5	TSL:1	n.557C>T		non_coding_transcript_exon	Exon 2 of 5	ENSP00000435950.1
SMPD1	ENST00000534405.5	TSL:1	n.557C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000434353.1

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151706

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:

0.0000589

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.0000243

AC:

AN:

164404

AF XY:

0.0000113

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000771

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000154

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000398

AC:

AN:

1406424

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

694964

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32062

American (AMR)

AF:

0.0000801

AC:

AN:

37448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25336

East Asian (EAS)

AF:

0.00

AC:

AN:

36696

South Asian (SAS)

AF:

0.0000125

AC:

AN:

80316

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4324

European-Non Finnish (NFE)

AF:

0.0000471

AC:

AN:

1083370

Other (OTH)

AF:

0.0000172

AC:

AN:

58194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.0000330

AC:

AN:

151706

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41324

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67898

Other (OTH)

AF:

0.000480

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

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:

0.0000712

Hom.:

Bravo

AF:

0.0000718

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Niemann-Pick disease, type B (4)

not provided (3)

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (2)

Niemann-Pick disease, type A (1)

SMPD1-related disorder (1)

Sphingomyelin/cholesterol lipidosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.0

PhyloP100

7.2

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-8.6

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Vest4

0.82

MVP

0.99

MPC

0.81

ClinPred

0.95

GERP RS

5.1

PromoterAI

0.024

Neutral

(source)

Varity_R

0.73

gMVP

0.93

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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