2-130152664-A-G

Variant names:

• chr2-130152664-A-G
• rs1461373312
• NM_017951.5:c.2375T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_017951.5(SMPD4):​c.2375T>C​(p.Leu792Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMPD4 NM_017951.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity NSMA3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD4	NM_017951.5	c.2375T>C	p.Leu792Pro	missense_variant	Exon 20 of 20	ENST00000680298.1	NP_060421.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD4	ENST00000680298.1	c.2375T>C	p.Leu792Pro	missense_variant	Exon 20 of 20		NM_017951.5	ENSP00000506463.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1414202 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 699230

African (AFR) AF: 0.00 AC: 0 AN: 32296

American (AMR) AF: 0.00 AC: 0 AN: 37370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25306

East Asian (EAS) AF: 0.00 AC: 0 AN: 36880

South Asian (SAS) AF: 0.00 AC: 0 AN: 80682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4898

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088576

Other (OTH) AF: 0.00 AC: 0 AN: 58558

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2492T>C (p.L831P) 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 2492, causing the leucine (L) at amino acid position 831 to be replaced by a proline (P). 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	0.44
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	-0.17	T
PhyloP100		3.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Vest4		0.62
MVP		0.65
MPC		1.2
ClinPred		0.96	D
GERP RS		4.1
Varity_R		0.79
gMVP		0.83
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs1461373312; hg19: chr2-130910237;