Genetic Variant NM_018667.4:c.1395G>A (chr16-68365021-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_018667.4(SMPD3):c.1395G>A(p.Pro465Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,613,752 control chromosomes in the GnomAD database, including 287,480 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.61 ( 28567 hom., cov: 32)

Exomes 𝑓: 0.59 ( 258913 hom. )

Consequence

SMPD3
NM_018667.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.340

Publications

33 publications found

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 was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP7

Synonymous conserved (PhyloP=-0.34 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD3	NM_018667.4 link	c.1395G>A	p.Pro465Pro	synonymous_variant	Exon 4 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.1395G>A	p.Pro465Pro	synonymous_variant	Exon 4 of 9	1	NM_018667.4	ENSP00000219334.5		Q9NY59-1

Frequencies

GnomAD3 genomes

AF:

0.610

AC:

92614

AN:

151926

Hom.:

28536

Cov.:

show subpopulations

Gnomad AFR

AF:

0.655

Gnomad AMI

AF:

0.497

Gnomad AMR

AF:

0.656

Gnomad ASJ

AF:

0.441

Gnomad EAS

AF:

0.785

Gnomad SAS

AF:

0.522

Gnomad FIN

AF:

0.521

Gnomad MID

AF:

0.491

Gnomad NFE

AF:

0.589

Gnomad OTH

AF:

0.601

GnomAD2 exomes

AF:

0.600

AC:

150359

AN:

250656

AF XY:

0.591

show subpopulations

Gnomad AFR exome

AF:

0.657

Gnomad AMR exome

AF:

0.704

Gnomad ASJ exome

AF:

0.452

Gnomad EAS exome

AF:

0.783

Gnomad FIN exome

AF:

0.532

Gnomad NFE exome

AF:

0.578

Gnomad OTH exome

AF:

0.573

GnomAD4 exome

AF:

0.593

AC:

866304

AN:

1461708

Hom.:

258913

Cov.:

AF XY:

0.589

AC XY:

428363

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.661

AC:

22131

AN:

33472

American (AMR)

AF:

0.696

AC:

31138

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.454

AC:

11853

AN:

26136

East Asian (EAS)

AF:

0.796

AC:

31609

AN:

39694

South Asian (SAS)

AF:

0.527

AC:

45481

AN:

86254

European-Finnish (FIN)

AF:

0.537

AC:

28630

AN:

53360

Middle Eastern (MID)

AF:

0.509

AC:

2935

AN:

5768

European-Non Finnish (NFE)

AF:

0.591

AC:

657174

AN:

1111928

Other (OTH)

AF:

0.585

AC:

35353

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

20322

40643

60965

81286

101608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18092

36184

54276

72368

90460

<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:

0.610

AC:

92689

AN:

152044

Hom.:

28567

Cov.:

AF XY:

0.606

AC XY:

44997

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.655

AC:

27168

AN:

41474

American (AMR)

AF:

0.656

AC:

10030

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.441

AC:

1529

AN:

3468

East Asian (EAS)

AF:

0.786

AC:

4062

AN:

5166

South Asian (SAS)

AF:

0.524

AC:

2519

AN:

4808

European-Finnish (FIN)

AF:

0.521

AC:

5510

AN:

10576

Middle Eastern (MID)

AF:

0.493

AC:

145

AN:

294

European-Non Finnish (NFE)

AF:

0.589

AC:

40021

AN:

67958

Other (OTH)

AF:

0.594

AC:

1253

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1840

3680

5521

7361

9201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

768

1536

2304

3072

3840

<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:

0.587

Hom.:

70943

Bravo

AF:

0.623

Asia WGS

AF:

0.579

AC:

2013

AN:

3478

EpiCase

AF:

0.572

EpiControl

AF:

0.572

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

4.6

(source)

DANN

Benign

0.93

PhyloP100

-0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over