rs375570126

chr11-6394482-C-Gchr11-6394482-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000543.5(SMPD1):c.1771C>G(p.Arg591Gly) variant causes a missense change. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R591C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.64

Genes affected

SMPD1 (HGNC:11120): (sphingomyelin phosphodiesterase 1) The protein encoded by this gene is a lysosomal acid sphingomyelinase that converts sphingomyelin to ceramide. The encoded protein also has phospholipase C activity. Defects in this gene are a cause of Niemann-Pick disease type A (NPA) and Niemann-Pick disease type B (NPB). Multiple transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000543.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.1771C>G	p.Arg591Gly	missense_variant	6/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.1771C>G	p.Arg591Gly	missense_variant	6/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461574 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.18	D
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.010	D;D
Vest4		0.47
MVP		0.94
MPC		0.53
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.66
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs375570126; hg19: chr11-6415712;