Genetic Variant NM_017951.5:c.2360T>C (chr2-130152679-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017951.5(SMPD4):c.2360T>C(p.Phe787Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,418,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. F787V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SMPD4
NM_017951.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD4	NM_017951.5 link	c.2360T>C	p.Phe787Ser	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.2360T>C	p.Phe787Ser	missense_variant	Exon 20 of 20		NM_017951.5	ENSP00000506463.1		A0A7P0TB24

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000282

AC:

AN:

1418838

Hom.:

Cov.:

AF XY:

0.00000427

AC XY:

AN XY:

702122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32430

American (AMR)

AF:

0.00

AC:

AN:

37940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25370

East Asian (EAS)

AF:

0.00

AC:

AN:

37236

South Asian (SAS)

AF:

0.00

AC:

AN:

81274

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49792

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4856

European-Non Finnish (NFE)

AF:

0.00000367

AC:

AN:

1091206

Other (OTH)

AF:

0.00

AC:

AN:

58734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 17, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2477T>C (p.F826S) 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 2477, causing the phenylalanine (F) at amino acid position 826 to be replaced by a serine (S). 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

Uncertain

0.40

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.046

Eigen_PC

Benign

-0.080

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.48

T;T;T

MetaSVM

Benign

-0.84

PhyloP100

1.9

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.011

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Vest4

0.45

MVP

0.33

MPC

1.1

ClinPred

0.98

GERP RS

2.9

Varity_R

0.28

gMVP

0.70

Mutation Taster

=68/32

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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NM_017951.5:c.2360T>C

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