Variant 6-122789368-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006714.5(SMPDL3A):c.22G>C(p.Val8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,547,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SMPDL3A
NM_006714.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.401

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0074439943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPDL3A	NM_006714.5 linkuse as main transcript	c.22G>C	p.Val8Leu	missense_variant	1/8	ENST00000368440.5
SMPDL3A	NM_001286138.2 linkuse as main transcript	c.-158G>C		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPDL3A	ENST00000368440.5 linkuse as main transcript	c.22G>C	p.Val8Leu	missense_variant	1/8	1	NM_006714.5	P1	Q92484-1
SMPDL3A	ENST00000539041.5 linkuse as main transcript	c.-158G>C		5_prime_UTR_variant	1/7	2			Q92484-2
SMPDL3A	ENST00000487215.1 linkuse as main transcript	n.77G>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

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:

0.000193

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

GnomAD3 exomes

AF:

0.0000209

AC:

AN:

143672

Hom.:

AF XY:

0.00

AC XY:

AN XY:

77352

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000410

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000949

Gnomad SAS exome

AF:

0.0000447

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000122

AC:

AN:

1395640

Hom.:

Cov.:

AF XY:

0.0000131

AC XY:

AN XY:

688360

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000281

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000506

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000278

Gnomad4 OTH exome

AF:

0.000155

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000629

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The c.22G>C (p.V8L) alteration is located in exon 1 (coding exon 1) of the SMPDL3A gene. This alteration results from a G to C substitution at nucleotide position 22, causing the valine (V) at amino acid position 8 to be replaced by a leucine (L). 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

0.097

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.76

Cadd

Benign

0.56

Dann

Benign

0.77

DEOGEN2

Benign

0.0055

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.51

M_CAP

Benign

0.0049

MetaRNN

Benign

0.0074

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

0.43

REVEL

Benign

0.027

Sift

Benign

0.52

Sift4G

Benign

0.88

Polyphen

0.0010

Vest4

0.054

MutPred

0.32

Loss of catalytic residue at V8 (P = 0.1065);

MVP

0.20

MPC

0.085

ClinPred

0.015

GERP RS

-0.20

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.048

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over