2-130152679-A-G

Variant names:

• chr2-130152679-A-G
• rs1686345847
• NM_017951.5:c.2360T>C

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93
• 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: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD4	NM_017951.5	MANE Select	c.2360T>C	p.Phe787Ser	missense	Exon 20 of 20	NP_060421.3	A0A7P0TB24
	SMPD4	NM_017751.4		c.2390T>C	p.Phe797Ser	missense	Exon 19 of 19	NP_060221.2	Q9NXE4-2
	SMPD4	NM_001171083.2		c.2171T>C	p.Phe724Ser	missense	Exon 17 of 17	NP_001164554.1	Q9NXE4-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD4	ENST00000680298.1	MANE Select	c.2360T>C	p.Phe787Ser	missense	Exon 20 of 20	ENSP00000506463.1	A0A7P0TB24
	SMPD4	ENST00000409031.5	TSL:1	c.2477T>C	p.Phe826Ser	missense	Exon 20 of 20	ENSP00000386531.1	Q9NXE4-1
	SMPD4	ENST00000454468.5	TSL:1	n.*2064T>C		non_coding_transcript_exon	Exon 19 of 19	ENSP00000407591.1	F8WF03

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1418838 Hom.: 0 Cov.: 31 AF XY: 0.00000427 AC XY: 3 AN XY: 702122

African (AFR) AF: 0.00 AC: 0 AN: 32430

American (AMR) AF: 0.00 AC: 0 AN: 37940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25370

East Asian (EAS) AF: 0.00 AC: 0 AN: 37236

South Asian (SAS) AF: 0.00 AC: 0 AN: 81274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4856

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1091206

Other (OTH) AF: 0.00 AC: 0 AN: 58734

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	-0.046
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.84	T
PhyloP100		1.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0030	D
Vest4		0.45
MVP		0.33
MPC		1.1
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.28
gMVP		0.70
Mutation Taster		=68/32	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: rs1686345847; hg19: chr2-130910252;