16-68370897-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_018667.4(SMPD3):​c.1285G>A​(p.Asp429Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000836 in 1,614,058 control chromosomes in the GnomAD database, including 3 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000085 ( 3 hom. )

Consequence

SMPD3
NM_018667.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0490
Variant links:
Genes affected
SMPD3 (HGNC:14240): (sphingomyelin phosphodiesterase 3) Predicted to enable phosphatidic acid binding activity; phosphatidylserine binding activity; and sphingomyelin phosphodiesterase activity. Predicted to be involved in positive regulation of exosomal secretion and sphingomyelin metabolic process. Predicted to act upstream of or within several processes, including animal organ development; enzyme linked receptor protein signaling pathway; and sphingolipid metabolic process. Predicted to be located in Golgi apparatus and plasma membrane. Predicted to be active in cytoplasm. Biomarker of pulmonary emphysema. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.052097708).
BS2
High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMPD3NM_018667.4 linkc.1285G>A p.Asp429Asn missense_variant Exon 3 of 9 ENST00000219334.10 NP_061137.1 Q9NY59-1A8K0T6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMPD3ENST00000219334.10 linkc.1285G>A p.Asp429Asn missense_variant Exon 3 of 9 1 NM_018667.4 ENSP00000219334.5 Q9NY59-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152214
Hom.:
0
Cov.:
33
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:
0.00115
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000104
AC:
26
AN:
250600
Hom.:
1
AF XY:
0.000125
AC XY:
17
AN XY:
135546
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000327
Gnomad SAS exome
AF:
0.000622
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000848
AC:
124
AN:
1461726
Hom.:
3
Cov.:
31
AF XY:
0.000103
AC XY:
75
AN XY:
727144
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000353
Gnomad4 SAS exome
AF:
0.000870
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000252
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152332
Hom.:
0
Cov.:
33
AF XY:
0.0000940
AC XY:
7
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 10, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1285G>A (p.D429N) alteration is located in exon 3 (coding exon 1) of the SMPD3 gene. This alteration results from a G to A substitution at nucleotide position 1285, causing the aspartic acid (D) at amino acid position 429 to be replaced by an asparagine (N). 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
0.073
BayesDel_addAF
Benign
-0.56
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
6.0
DANN
Benign
0.79
DEOGEN2
Benign
0.32
T;T;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.044
N
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Benign
0.0072
T
MetaRNN
Benign
0.052
T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.34
N;.;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-1.4
N;N;N
REVEL
Benign
0.0040
Sift
Benign
0.097
T;T;T
Sift4G
Benign
0.11
T;T;T
Polyphen
0.0070
B;.;.
Vest4
0.12
MutPred
0.35
Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);
MVP
0.39
MPC
0.20
ClinPred
0.063
T
GERP RS
-6.9
Varity_R
0.13
gMVP
0.33

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

LitVar

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

Other links and lift over

dbSNP: rs572684927; hg19: chr16-68404800; COSMIC: COSV54715512; COSMIC: COSV54715512; API