dbSNP rs28385609: SMPDL3A:p.Pro161Ala (chr6-122801319-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006714.5(SMPDL3A):c.481C>G(p.Pro161Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,610,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SMPDL3A
NM_006714.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.57

Publications

26 publications found

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]

SMPDL3A links:

ENSG00000294893 (HGNC:):

ENSG00000294893 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPDL3A	NM_006714.5 link	c.481C>G	p.Pro161Ala	missense_variant	Exon 4 of 8	ENST00000368440.5	NP_006705.1	Q92484-1
SMPDL3A	NM_001286138.2 link	c.88C>G	p.Pro30Ala	missense_variant	Exon 3 of 7		NP_001273067.1	Q92484-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMPDL3A	ENST00000368440.5 link	c.481C>G	p.Pro161Ala	missense_variant	Exon 4 of 8	1	NM_006714.5	ENSP00000357425.4	Q92484-1
SMPDL3A	ENST00000539041.5 link	c.88C>G	p.Pro30Ala	missense_variant	Exon 3 of 7	2		ENSP00000442152.1	Q92484-2
ENSG00000294893	ENST00000726593.1 link	n.331-19982G>C		intron_variant	Intron 1 of 1
ENSG00000294893	ENST00000726594.1 link	n.314+12984G>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

6.86e-7

AC:

AN:

1458034

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725544

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108718

Other (OTH)

AF:

0.00

AC:

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

4868

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

-0.027

MutationAssessor

Uncertain

2.1

.;M

PhyloP100

6.6

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.63

MutPred

0.49

.;Loss of methylation at K166 (P = 0.0654);

MVP

0.88

MPC

0.47

ClinPred

1.0

GERP RS

5.7

Varity_R

0.83

gMVP

0.80

Mutation Taster

=75/25

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over