chr2-130152671-C-T

Variant names:

• chr2-130152671-C-T
• rs1261894118
• NM_017951.5:c.2368G>A

Variant summary

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

The NM_017951.5(SMPD4):​c.2368G>A​(p.Ala790Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 1,568,296 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (1 hom.)
• Consequence: SMPD4 NM_017951.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24729201).

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.2368G>A	p.Ala790Thr	missense	Exon 20 of 20	NP_060421.3	A0A7P0TB24
	SMPD4	NM_017751.4		c.2398G>A	p.Ala800Thr	missense	Exon 19 of 19	NP_060221.2	Q9NXE4-2
	SMPD4	NM_001171083.2		c.2179G>A	p.Ala727Thr	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.2368G>A	p.Ala790Thr	missense	Exon 20 of 20	ENSP00000506463.1	A0A7P0TB24
	SMPD4	ENST00000409031.5	TSL:1	c.2485G>A	p.Ala829Thr	missense	Exon 20 of 20	ENSP00000386531.1	Q9NXE4-1
	SMPD4	ENST00000454468.5	TSL:1	n.*2072G>A		non_coding_transcript_exon	Exon 19 of 19	ENSP00000407591.1	F8WF03

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000191 AC: 27 AN: 1416108 Hom.: 1 Cov.: 31 AF XY: 0.0000143 AC XY: 10 AN XY: 700408

African (AFR) AF: 0.00 AC: 0 AN: 32360

American (AMR) AF: 0.00 AC: 0 AN: 37644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25340

East Asian (EAS) AF: 0.00 AC: 0 AN: 37010

South Asian (SAS) AF: 0.00 AC: 0 AN: 80910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4876

European-Non Finnish (NFE) AF: 0.0000248 AC: 27 AN: 1089662

Other (OTH) AF: 0.00 AC: 0 AN: 58610

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

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	Benign	0.21
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Benign	0.071
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.74	T
PhyloP100		2.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.23
Sift	Benign	0.073	T
Sift4G	Benign	0.11	T
Vest4		0.13
MVP		0.47
MPC		0.85
ClinPred		0.72	D
GERP RS		3.2
Varity_R		0.071
gMVP		0.41
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1261894118; hg19: chr2-130910244;