NM_017951.5:c.2301C>T

Variant names:

• chr2-130152738-G-A
• NM_017951.5:c.2301C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4 BP6_Moderate BP7

The NM_017951.5(SMPD4):​c.2301C>T​(p.Pro767Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,438,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMPD4 NM_017951.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.787
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.26).
• BP6: Variant 2-130152738-G-A is Benign according to our data. Variant chr2-130152738-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3026067.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.787 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD4	NM_017951.5	c.2301C>T	p.Pro767Pro	synonymous_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.2301C>T	p.Pro767Pro	synonymous_variant	Exon 20 of 20		NM_017951.5	ENSP00000506463.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438924 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 2 AN XY: 713962

African (AFR) AF: 0.00 AC: 0 AN: 33100

American (AMR) AF: 0.00 AC: 0 AN: 40682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25628

East Asian (EAS) AF: 0.00 AC: 0 AN: 38656

South Asian (SAS) AF: 0.00 AC: 0 AN: 83680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5008

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102138

Other (OTH) AF: 0.00 AC: 0 AN: 59440

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMPD4: PM2:Supporting, BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.7
DANN	Benign	0.65
PhyloP100		-0.79
Mutation Taster		=100/0	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

hg19: chr2-130910311;