Genetic Variant NM_017951.5:c.2366T>C (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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V789M) has been classified 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: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017951.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMPD4	NM_017951.5	MANE Select	c.2366T>C	p.Val789Ala	missense	Exon 20 of 20	NP_060421.3	A0A7P0TB24
SMPD4	NM_017751.4		c.2396T>C	p.Val799Ala	missense	Exon 19 of 19	NP_060221.2	Q9NXE4-2
SMPD4	NM_001171083.2		c.2177T>C	p.Val726Ala	missense	Exon 17 of 17	NP_001164554.1	Q9NXE4-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMPD4	ENST00000680298.1	MANE Select	c.2366T>C	p.Val789Ala	missense	Exon 20 of 20	ENSP00000506463.1	A0A7P0TB24
SMPD4	ENST00000409031.5	TSL:1	c.2483T>C	p.Val828Ala	missense	Exon 20 of 20	ENSP00000386531.1	Q9NXE4-1
SMPD4	ENST00000454468.5	TSL:1	n.*2070T>C		non_coding_transcript_exon	Exon 19 of 19	ENSP00000407591.1	F8WF03

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

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

Cov.:

ExAC

AF:

0.0000253

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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

M_CAP

Benign

0.017

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.0

PhyloP100

3.6

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.37

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.029

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over