Variant 1-27953302-T-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_014474.4(SMPDL3B):c.461T>G(p.Ile154Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

SMPDL3B
NM_014474.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.71

Variant links:

Genes affected

SMPDL3B (HGNC:21416): (sphingomyelin phosphodiesterase acid like 3B) Enables phosphoric diester hydrolase activity. Predicted to be involved in membrane lipid catabolic process; negative regulation of inflammatory response; and negative regulation of toll-like receptor signaling pathway. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

SMPDL3B links:

(HGNC:):

links:

Genome browser will be placed here

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/exons	MANE
SMPDL3B	NM_014474.4 linkuse as main transcript	c.461T>G	p.Ile154Arg	missense_variant	4/8	ENST00000373894.8
SMPDL3B	NM_001009568.3 linkuse as main transcript	c.461T>G	p.Ile154Arg	missense_variant	4/7
SMPDL3B	XM_011541259.3 linkuse as main transcript	c.551T>G	p.Ile184Arg	missense_variant	5/9
SMPDL3B	NM_001304579.2 linkuse as main transcript	c.-158T>G		5_prime_UTR_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPDL3B	ENST00000373894.8 linkuse as main transcript	c.461T>G	p.Ile154Arg	missense_variant	4/8	1	NM_014474.4	P1	Q92485-1
	ENST00000448015.1 linkuse as main transcript	n.286+2469A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251356

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000889

AC:

130

AN:

1461634

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000105

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000481

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:

0.000162

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.0000893

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

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

Aug 09, 2021

The c.461T>G (p.I154R) alteration is located in exon 4 (coding exon 4) of the SMPDL3B gene. This alteration results from a T to G substitution at nucleotide position 461, causing the isoleucine (I) at amino acid position 154 to be replaced by an arginine (R). 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

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.50

D;D;.

Eigen

Benign

0.085

Eigen_PC

Benign

-0.051

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.83

T;T;T

M_CAP

Uncertain

0.092

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Uncertain

0.25

MutationAssessor

Uncertain

2.3

M;.;M

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-4.5

D;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.97

D;.;D

Vest4

0.70

MVP

0.92

MPC

1.1

ClinPred

0.54

GERP RS

4.0

Varity_R

0.57

gMVP

0.92

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.

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