2-130152742-C-G

Variant names:

• chr2-130152742-C-G
• rs762144739
• NM_017951.5:c.2297G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017951.5(SMPD4):​c.2297G>C​(p.Gly766Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,439,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. G766S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SMPD4 NM_017951.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2793811).

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.2297G>C	p.Gly766Ala	missense	Exon 20 of 20	NP_060421.3	A0A7P0TB24
	SMPD4	NM_017751.4		c.2327G>C	p.Gly776Ala	missense	Exon 19 of 19	NP_060221.2	Q9NXE4-2
	SMPD4	NM_001171083.2		c.2108G>C	p.Gly703Ala	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.2297G>C	p.Gly766Ala	missense	Exon 20 of 20	ENSP00000506463.1	A0A7P0TB24
	SMPD4	ENST00000409031.5	TSL:1	c.2414G>C	p.Gly805Ala	missense	Exon 20 of 20	ENSP00000386531.1	Q9NXE4-1
	SMPD4	ENST00000454468.5	TSL:1	n.*2001G>C		non_coding_transcript_exon	Exon 19 of 19	ENSP00000407591.1	F8WF03

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1439926 Hom.: 0 Cov.: 31 AF XY: 0.00000840 AC XY: 6 AN XY: 714610

African (AFR) AF: 0.00 AC: 0 AN: 33134

American (AMR) AF: 0.00 AC: 0 AN: 40880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25634

East Asian (EAS) AF: 0.00 AC: 0 AN: 38730

South Asian (SAS) AF: 0.00 AC: 0 AN: 83770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5012

European-Non Finnish (NFE) AF: 0.0000145 AC: 16 AN: 1102678

Other (OTH) AF: 0.0000168 AC: 1 AN: 59488

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000283 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.12
Sift	Benign	0.30	T
Sift4G	Benign	0.37	T
Vest4		0.40
MVP		0.40
MPC		0.94
ClinPred		0.53	D
GERP RS		4.6
Varity_R		0.098
gMVP		0.36
Mutation Taster		=91/9	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: rs762144739; hg19: chr2-130910315;