6-109443332-G-T

Variant names:

• chr6-109443332-G-T
• rs1476387
• NM_003080.3:c.795G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003080.3(SMPD2):​c.795G>T​(p.Arg265Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,612,770 control chromosomes in the GnomAD database, including 162,872 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (21333 hom., cov: 32)
  • Exomes 𝑓: 0.44 (141539 hom.)
• Consequence: SMPD2 NM_003080.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.473
• Publications: 56 publications found

Genes affected

SMPD2 (HGNC:11121): (sphingomyelin phosphodiesterase 2) This gene encodes a protein which was initially identified as a sphingomyelinase based on sequence similarity between bacterial sphingomyelinases and a yeast protein. Subsequent studies showed that its biological function is less likely to be as a sphingomyelinase and instead as a lysophospholipase. [provided by RefSeq, Oct 2009]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.225618E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD2	NM_003080.3	c.795G>T	p.Arg265Ser	missense_variant	Exon 9 of 10	ENST00000258052.8	NP_003071.2
SMPD2	XM_011536079.2	c.480G>T	p.Arg160Ser	missense_variant	Exon 7 of 8		XP_011534381.1
SMPD2	XR_942566.3	n.1128G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD2	ENST00000258052.8	c.795G>T	p.Arg265Ser	missense_variant	Exon 9 of 10	1	NM_003080.3	ENSP00000258052.3
SMPD2	ENST00000458487.1	c.483G>T	p.Arg161Ser	missense_variant	Exon 3 of 4	2		ENSP00000399731.1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78220 AN: 151858 Hom.: 21293 Cov.: 32

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.489

GnomAD2 exomes AF: 0.475 AC: 119332 AN: 251394 AF XY: 0.473

Gnomad AFR exome AF: 0.713

Gnomad AMR exome AF: 0.490

Gnomad ASJ exome AF: 0.514

Gnomad EAS exome AF: 0.470

Gnomad FIN exome AF: 0.470

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.461

GnomAD4 exome AF: 0.435 AC: 636030 AN: 1460794 Hom.: 141539 Cov.: 40 AF XY: 0.438 AC XY: 318162 AN XY: 726714

African (AFR) AF: 0.716 AC: 23946 AN: 33466

American (AMR) AF: 0.489 AC: 21868 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 13460 AN: 26132

East Asian (EAS) AF: 0.511 AC: 20263 AN: 39690

South Asian (SAS) AF: 0.534 AC: 46092 AN: 86238

European-Finnish (FIN) AF: 0.470 AC: 25078 AN: 53358

Middle Eastern (MID) AF: 0.501 AC: 2889 AN: 5766

European-Non Finnish (NFE) AF: 0.409 AC: 454756 AN: 1111050

Other (OTH) AF: 0.458 AC: 27678 AN: 60370

GnomAD4 genome AF: 0.515 AC: 78322 AN: 151976 Hom.: 21333 Cov.: 32 AF XY: 0.517 AC XY: 38417 AN XY: 74278

African (AFR) AF: 0.708 AC: 29340 AN: 41424

American (AMR) AF: 0.505 AC: 7721 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1777 AN: 3470

East Asian (EAS) AF: 0.486 AC: 2506 AN: 5152

South Asian (SAS) AF: 0.533 AC: 2565 AN: 4812

European-Finnish (FIN) AF: 0.465 AC: 4909 AN: 10556

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27990 AN: 67962

Other (OTH) AF: 0.490 AC: 1034 AN: 2112

Alfa AF: 0.447 Hom.: 49848

Bravo AF: 0.525

TwinsUK AF: 0.419 AC: 1553

ALSPAC AF: 0.401 AC: 1546

ESP6500AA AF: 0.697 AC: 3071

ESP6500EA AF: 0.422 AC: 3627

ExAC AF: 0.476 AC: 57854

Asia WGS AF: 0.538 AC: 1871 AN: 3478

EpiCase AF: 0.423

EpiControl AF: 0.424

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.017
DANN	Benign	0.37
DEOGEN2	Benign	0.18	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-0.47
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.28
Sift	Benign	0.63	T
Sift4G	Benign	0.72	T
Vest4		0.020
ClinPred		0.0033	T
GERP RS		-7.3
Varity_R		0.10
gMVP		0.39
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1476387; hg19: chr6-109764535; COSMIC: COSV57807479; COSMIC: COSV57807479;