rs778492516

Variant names:

• chr16-68370902-C-A
• rs778492516
• NM_018667.4:c.1280G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-68370902-C-A
• chr16-68370902-C-G
• chr16-68370902-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018667.4(SMPD3):​c.1280G>T​(p.Cys427Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C427Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SMPD3 NM_018667.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.239
• Publications: 1 publications found

Genes affected

SMPD3 (HGNC:14240): (sphingomyelin phosphodiesterase 3) Predicted to enable phosphatidic acid binding activity; phosphatidylserine binding activity; and sphingomyelin phosphodiesterase activity. Predicted to be involved in positive regulation of exosomal secretion and sphingomyelin metabolic process. Predicted to act upstream of or within several processes, including animal organ development; enzyme linked receptor protein signaling pathway; and sphingolipid metabolic process. Predicted to be located in Golgi apparatus and plasma membrane. Predicted to be active in cytoplasm. Biomarker of pulmonary emphysema. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09899226).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018667.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD3	NM_018667.4	MANE Select	c.1280G>T	p.Cys427Phe	missense	Exon 3 of 9	NP_061137.1	Q9NY59-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD3	ENST00000219334.10	TSL:1 MANE Select	c.1280G>T	p.Cys427Phe	missense	Exon 3 of 9	ENSP00000219334.5	Q9NY59-1
	SMPD3	ENST00000563226.1	TSL:1	c.1280G>T	p.Cys427Phe	missense	Exon 1 of 7	ENSP00000455955.1	Q9NY59-2
	SMPD3	ENST00000568373.5	TSL:1	c.1280G>T	p.Cys427Phe	missense	Exon 1 of 7	ENSP00000457422.1	H3BS51

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461782 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.78
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.24
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.019	D
Polyphen		0.24	B
Vest4		0.18
MutPred		0.49		Loss of helix (P = 0.0093)
MVP		0.18
MPC		0.31
ClinPred		0.13	T
GERP RS		1.7
PromoterAI		0.017	Neutral
Varity_R		0.24
gMVP		0.69
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs778492516; hg19: chr16-68404805;