11-6391795-G-C

Variant names:

• chr11-6391795-G-C
• NM_000543.5:c.730G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1 PM1 PM2 PP3_Moderate

The NM_000543.5(SMPD1):​c.730G>C​(p.Gly244Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.25

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 Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_000543.5 (SMPD1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a disulfide_bond (size 23) in uniprot entity ASM_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_000543.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.730G>C	p.Gly244Arg	missense_variant	Exon 2 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.730G>C	p.Gly244Arg	missense_variant	Exon 2 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460226 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726520

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.73	T
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.92
MVP		0.64
MPC		0.88
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-6413025;