rs898339985

Variant summary

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

The NM_006714.5(SMPDL3A):​c.541G>A​(p.Glu181Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,611,728 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 (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SMPDL3A
NM_006714.5 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.04
Variant links:
Genes affected
SMPDL3A (HGNC:17389): (sphingomyelin phosphodiesterase acid like 3A) Enables phosphoric diester hydrolase activity and zinc ion binding activity. Involved in nucleoside triphosphate catabolic process. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

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 rank MANE Protein UniProt
SMPDL3ANM_006714.5 linkc.541G>A p.Glu181Lys missense_variant Exon 4 of 8 ENST00000368440.5 NP_006705.1 Q92484-1
SMPDL3ANM_001286138.2 linkc.148G>A p.Glu50Lys missense_variant Exon 3 of 7 NP_001273067.1 Q92484-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMPDL3AENST00000368440.5 linkc.541G>A p.Glu181Lys missense_variant Exon 4 of 8 1 NM_006714.5 ENSP00000357425.4 Q92484-1
SMPDL3AENST00000539041.5 linkc.148G>A p.Glu50Lys missense_variant Exon 3 of 7 2 ENSP00000442152.1 Q92484-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1459514
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
726260
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 NFE exome
AF:
9.01e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000189

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 18, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.541G>A (p.E181K) alteration is located in exon 4 (coding exon 4) of the SMPDL3A gene. This alteration results from a G to A substitution at nucleotide position 541, causing the glutamic acid (E) at amino acid position 181 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
.;T
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.30
T;T
MetaSVM
Uncertain
0.19
D
MutationAssessor
Benign
1.6
.;L
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.1
N;N
REVEL
Uncertain
0.52
Sift
Benign
0.31
T;T
Sift4G
Benign
0.79
T;T
Polyphen
0.97
.;D
Vest4
0.25
MutPred
0.49
.;Gain of MoRF binding (P = 0.0139);
MVP
0.95
MPC
0.37
ClinPred
0.77
D
GERP RS
5.7
Varity_R
0.68
gMVP
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.23
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.23
Position offset: 27

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: rs898339985; hg19: chr6-123122524; API