11-6394386-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000543.5(SMPD1):​c.1675G>T​(p.Val559Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 missense

Scores

1
3
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.366
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMPD1NM_000543.5 linkc.1675G>T p.Val559Leu missense_variant 6/6 ENST00000342245.9 NP_000534.3 P17405-1Q59EN6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMPD1ENST00000342245.9 linkc.1675G>T p.Val559Leu missense_variant 6/61 NM_000543.5 ENSP00000340409.4 P17405-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461886
Hom.:
0
Cov.:
34
AF XY:
0.00000275
AC XY:
2
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Benign
19
DANN
Benign
0.97
Eigen
Benign
-0.012
Eigen_PC
Benign
0.057
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.78
T;T
M_CAP
Benign
0.030
D
MetaRNN
Uncertain
0.55
D;D
MetaSVM
Benign
-1.1
T
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.70
N;N
REVEL
Uncertain
0.50
Sift
Benign
0.23
T;T
Sift4G
Benign
0.34
T;T
Vest4
0.68
MVP
0.97
MPC
0.22
ClinPred
0.21
T
GERP RS
4.9
Varity_R
0.23
gMVP
0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149939736; hg19: chr11-6415616; API