Genetic Variant SMPD4:p.Val789Ala (chr2-130152673-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_017951.5(SMPD4):c.2366T>C(p.Val789Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000162 in 1,416,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SMPD4
NM_017951.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.61

Publications

1 publications found

Variant links:

Genes affected

SMPD4 (HGNC:32949): (sphingomyelin phosphodiesterase 4) The protein encoded by this gene is a sphingomyelinase that catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide. This gene is activated by DNA damage, cellular stress, and tumor necrosis factor, but it is downregulated by wild-type p53. The encoded protein localizes to the endoplasmic reticulum and Golgi network. [provided by RefSeq, Mar 2017]

SMPD4 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

SMPD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1965006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD4	NM_017951.5 link	c.2366T>C	p.Val789Ala	missense_variant	Exon 20 of 20	ENST00000680298.1	NP_060421.3	Q9NXE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD4	ENST00000680298.1 link	c.2366T>C	p.Val789Ala	missense_variant	Exon 20 of 20		NM_017951.5	ENSP00000506463.1		A0A7P0TB24

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000227

AC:

AN:

175958

AF XY:

0.0000213

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000162

AC:

AN:

1416786

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

700838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32384

American (AMR)

AF:

0.00

AC:

AN:

37712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25356

East Asian (EAS)

AF:

0.00

AC:

AN:

37074

South Asian (SAS)

AF:

0.000284

AC:

AN:

81010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4876

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090014

Other (OTH)

AF:

0.00

AC:

AN:

58630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000253

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2483T>C (p.V828A) alteration is located in exon 20 (coding exon 20) of the SMPD4 gene. This alteration results from a T to C substitution at nucleotide position 2483, causing the valine (V) at amino acid position 828 to be replaced by an alanine (A). 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

0.14

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.037

Eigen_PC

Benign

-0.074

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

3.6

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.029

D;D;D

Vest4

0.25

MVP

0.41

MPC

0.81

ClinPred

0.40

GERP RS

2.8

Varity_R

0.12

gMVP

0.41

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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chr2-130152673-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over