chr11-6390705-TGCTGGCGCTGGC-T

Position:

• chr11-6390705-TGCTGGCGCTGGC-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP6

The ENST00000342245.9(SMPD1):​c.132_143delGCTGGCGCTGGC​(p.Leu45_Ala48del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,595,110 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A44A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00050 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SMPD1 ENST00000342245.9 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.65

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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, 6 uncertain in ENST00000342245.9
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-6390705-TGCTGGCGCTGGC-T is Benign according to our data. Variant chr11-6390705-TGCTGGCGCTGGC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256591.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.132_143delGCTGGCGCTGGC	p.Leu45_Ala48del	disruptive_inframe_deletion	1/6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.132_143delGCTGGCGCTGGC	p.Leu45_Ala48del	disruptive_inframe_deletion	1/6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.000475 AC: 70 AN: 147228 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000404

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000197

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000177 AC: 256 AN: 1447756 Hom.: 0 AF XY: 0.000171 AC XY: 123 AN XY: 720014

Gnomad4 AFR exome AF: 0.00127

Gnomad4 AMR exome AF: 0.000226

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000163

Gnomad4 OTH exome AF: 0.000251

GnomAD4 genome AF: 0.000502 AC: 74 AN: 147354 Hom.: 1 Cov.: 0 AF XY: 0.000583 AC XY: 42 AN XY: 71998

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.000404

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000197

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Mar 20, 2017	Normal variation in repetative sequence -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

This variant, c.132_143del, results in the deletion of 4 amino acid(s) of the SMPD1 protein (p.Ala46_Leu49del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 256591). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 21, 2020

This variant is associated with the following publications: (PMID: 7727545) -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3838786; hg19: chr11-6411935;