rs143175313

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-130152582-G-A
• chr2-130152582-G-C
• chr2-130152582-G-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: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

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 VariationId 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

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.2457C>T	p.Thr819Thr	synonymous	Exon 20 of 20	NP_060421.3	A0A7P0TB24
	SMPD4	NM_017751.4		c.2487C>T	p.Thr829Thr	synonymous	Exon 19 of 19	NP_060221.2	Q9NXE4-2
	SMPD4	NM_001171083.2		c.2268C>T	p.Thr756Thr	synonymous	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.2457C>T	p.Thr819Thr	synonymous	Exon 20 of 20	ENSP00000506463.1	A0A7P0TB24
	SMPD4	ENST00000409031.5	TSL:1	c.2574C>T	p.Thr858Thr	synonymous	Exon 20 of 20	ENSP00000386531.1	Q9NXE4-1
	SMPD4	ENST00000454468.5	TSL:1	n.*2161C>T		non_coding_transcript_exon	Exon 19 of 19	ENSP00000407591.1	F8WF03

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;