dbSNP rs755175875: SMPD3:p.Arg595Leu (chr16-68361685-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_018667.4(SMPD3):c.1784G>T(p.Arg595Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,510 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R595Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SMPD3
NM_018667.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.46

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]

SMPD3 links:

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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 rank	MANE	Protein	UniProt
SMPD3	NM_018667.4 link	c.1784G>T	p.Arg595Leu	missense_variant	Exon 8 of 9	ENST00000219334.10	NP_061137.1	Q9NY59-1A8K0T6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD3	ENST00000219334.10 link	c.1784G>T	p.Arg595Leu	missense_variant	Exon 8 of 9	1	NM_018667.4	ENSP00000219334.5		Q9NY59-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250696

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000274

AC:

AN:

1460510

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726598

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;D;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.090

MetaRNN

Uncertain

0.62

D;D;D

MetaSVM

Benign

-0.97

MutationAssessor

Benign

2.0

M;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.5

N;D;N

REVEL

Benign

0.19

Sift

Benign

0.47

T;D;T

Sift4G

Benign

0.68

T;D;T

Polyphen

1.0

D;.;.

Vest4

0.66

MutPred

0.47

Loss of MoRF binding (P = 0.0299);.;.;

MVP

0.63

MPC

0.88

ClinPred

0.95

GERP RS

4.9

Varity_R

0.69

gMVP

0.72

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over