rs786204506

Variant names:

• chr11-6390694-G-A
• rs786204506
• NM_000543.5:c.96G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-6390694-G-A
• chr11-6390694-G-C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000543.5(SMPD1):​c.96G>A​(p.Trp32*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001370598: Publications reported experimental evidence evaluating an impact on protein function, demonstrating a residual enzyme activity of ~20% in leukocytes derived from a homozygous patient (Pittis_2004), though a complete lack of enzyme activity was reported in a eukaryotic cell expression system (Dardis_2005)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SMPD1 NM_000543.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.54
• Publications: 11 publications found

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]

SMPD1 Gene-Disease associations (from GenCC):

• acid sphingomyelinase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Niemann-Pick disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Niemann-Pick disease type A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia, G2P
• Niemann-Pick disease type B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 371 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001370598: Publications reported experimental evidence evaluating an impact on protein function, demonstrating a residual enzyme activity of ~20% in leukocytes derived from a homozygous patient (Pittis_2004), though a complete lack of enzyme activity was reported in a eukaryotic cell expression system (Dardis_2005).; SCV007105891: "Well-established in vitro and in vivo functional studies supportive of damaging effect on the gene product, with no residual enzymatic activity relative to wild-type reported" (PMID: 15241805, 16010684); SCV004758120: "In vitro experimental studies suggest this variant decreases enzymatic activity of the protein (Dardis et al. 2005. PubMed ID: 16010684)."
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-6390694-G-A is Pathogenic according to our data. Variant chr11-6390694-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 188840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000543.5. 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
	SMPD1	NM_000543.5	MANE Select	c.96G>A	p.Trp32*	stop_gained	Exon 1 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.96G>A	p.Trp32*	stop_gained	Exon 1 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.96G>A	p.Trp32*	stop_gained	Exon 1 of 5	NP_001352064.1	P17405-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.96G>A	p.Trp32*	stop_gained	Exon 1 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000531303.5	TSL:1	n.96G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000432625.1	E9PPK6
	SMPD1	ENST00000533123.5	TSL:1	n.96G>A		non_coding_transcript_exon	Exon 1 of 5	ENSP00000435950.1	G3V1E1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460436 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726430

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 85810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53112

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111650

Other (OTH) AF: 0.0000332 AC: 2 AN: 60310

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Niemann-Pick disease, type A (4)
3	-	-	Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (3)
1	-	-	Niemann-Pick disease, type B (1)
1	-	-	SMPD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.27	N
PhyloP100		3.5
Vest4		0.71
GERP RS		4.0
PromoterAI		0.019	Neutral
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs786204506; hg19: chr11-6411924;