11-6390705-TGCTGGCGCTGGCGCTGGCGCTGGC-TGCTGGCGCTGGCGCTGGCGCTGGCGCTGGC

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000543.5(SMPD1):c.138_143dup(p.Ala48_Leu49dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V36V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 0)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: SMPD1 NM_000543.5 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.158

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 Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 11-6390705-T-TGCTGGC is Benign according to our data. Variant chr11-6390705-T-TGCTGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 971581.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.138_143dup	p.Ala48_Leu49dup	inframe_insertion	1/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.138_143dup	p.Ala48_Leu49dup	inframe_insertion	1/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 180 AN: 147226 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000472

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: 0.0000455

Gnomad OTH AF: 0.00149

GnomAD4 exome AF: 0.000180 AC: 260 AN: 1447740 Hom.: 2 Cov.: 0 AF XY: 0.000144 AC XY: 104 AN XY: 720002

Gnomad4 AFR exome AF: 0.00453

Gnomad4 AMR exome AF: 0.000271

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: 0.0000372

Gnomad4 OTH exome AF: 0.000737

GnomAD4 genome AF: 0.00127 AC: 187 AN: 147352 Hom.: 2 Cov.: 0 AF XY: 0.00131 AC XY: 94 AN XY: 71996

Gnomad4 AFR AF: 0.00433

Gnomad4 AMR AF: 0.000471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000455

Gnomad4 OTH AF: 0.00147

Bravo AF: 0.00147

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 09, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2021	In-frame insertion of 2 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2022

This variant, c.138_143dup, results in the insertion of 2 amino acid(s) of the SMPD1 protein (p.Ala48_Leu49dup), 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: 971581). 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. -

SMPD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;