2-130152675-G-A

Variant names:

• chr2-130152675-G-A
• rs377045978
• NM_017951.5:c.2364C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_017951.5(SMPD4):​c.2364C>T​(p.Phe788Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00094 in 1,569,748 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00091 (3 hom.)
• Consequence: SMPD4 NM_017951.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0570
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.05).
• BP6: Variant 2-130152675-G-A is Benign according to our data. Variant chr2-130152675-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3387958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.057 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00119 (181/152338) while in subpopulation NFE AF = 0.00194 (132/68016). AF 95% confidence interval is 0.00167. There are 0 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD4	NM_017951.5	c.2364C>T	p.Phe788Phe	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.2364C>T	p.Phe788Phe	synonymous_variant	Exon 20 of 20		NM_017951.5	ENSP00000506463.1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000970 AC: 171 AN: 176300 AF XY: 0.000988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000152

Gnomad ASJ exome AF: 0.000345

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00283

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.000630

GnomAD4 exome AF: 0.000914 AC: 1295 AN: 1417410 Hom.: 3 Cov.: 31 AF XY: 0.000967 AC XY: 678 AN XY: 701224

African (AFR) AF: 0.0000617 AC: 2 AN: 32396

American (AMR) AF: 0.000238 AC: 9 AN: 37756

Ashkenazi Jewish (ASJ) AF: 0.000237 AC: 6 AN: 25364

East Asian (EAS) AF: 0.00 AC: 0 AN: 37118

South Asian (SAS) AF: 0.0000370 AC: 3 AN: 81114

European-Finnish (FIN) AF: 0.00259 AC: 129 AN: 49730

Middle Eastern (MID) AF: 0.000411 AC: 2 AN: 4866

European-Non Finnish (NFE) AF: 0.00101 AC: 1101 AN: 1090410

Other (OTH) AF: 0.000733 AC: 43 AN: 58656

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.00110 AC XY: 82 AN XY: 74494

African (AFR) AF: 0.000120 AC: 5 AN: 41582

American (AMR) AF: 0.000719 AC: 11 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00194 AC: 132 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMPD4: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.76
DANN	Benign	0.41
PhyloP100		0.057
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

dbSNP: rs377045978; hg19: chr2-130910248;