2-130152582-G-A

Variant names:

• chr2-130152582-G-A
• rs143175313
• NM_017951.5:c.2457C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_017951.5(SMPD4):​c.2457C>T​(p.Thr819Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,548,936 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (18 hom.)
• Consequence: SMPD4 NM_017951.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.95
• 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.004).
• BP6: Variant 2-130152582-G-A is Benign according to our data. Variant chr2-130152582-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2651354.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00234 (357/152334) while in subpopulation NFE AF = 0.00417 (284/68032). AF 95% confidence interval is 0.00377. There are 0 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD4	NM_017951.5	c.2457C>T	p.Thr819Thr	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.2457C>T	p.Thr819Thr	synonymous_variant	Exon 20 of 20		NM_017951.5	ENSP00000506463.1

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 357 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00417

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00207 AC: 325 AN: 156972 AF XY: 0.00198

Gnomad AFR exome AF: 0.000342

Gnomad AMR exome AF: 0.000404

Gnomad ASJ exome AF: 0.00212

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000565

Gnomad NFE exome AF: 0.00451

Gnomad OTH exome AF: 0.00226

GnomAD4 exome AF: 0.00382 AC: 5332 AN: 1396602 Hom.: 18 Cov.: 31 AF XY: 0.00370 AC XY: 2551 AN XY: 688676

African (AFR) AF: 0.000380 AC: 12 AN: 31548

American (AMR) AF: 0.000560 AC: 20 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.00171 AC: 43 AN: 25168

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35764

South Asian (SAS) AF: 0.000126 AC: 10 AN: 79178

European-Finnish (FIN) AF: 0.000842 AC: 41 AN: 48698

Middle Eastern (MID) AF: 0.000215 AC: 1 AN: 4644

European-Non Finnish (NFE) AF: 0.00467 AC: 5036 AN: 1078048

Other (OTH) AF: 0.00290 AC: 168 AN: 57862

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.00201 AC XY: 150 AN XY: 74488

African (AFR) AF: 0.000577 AC: 24 AN: 41578

American (AMR) AF: 0.00189 AC: 29 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00417 AC: 284 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00192 Hom.: 1

Bravo AF: 0.00243

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 01, 2023

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	-0.88
CADD	Benign	0.0040
DANN	Benign	0.43
PhyloP100		-5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs143175313; hg19: chr2-130910155;