11-6390705-TGCTGGCGCTGGCGCTGGCGCTGGC-TGCTGGC

Position:

• chr11-6390705-TGCTGGCGCTGGCGCTGGCGCTGGC-TGCTGGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000543.5(SMPD1):​c.126_143del​(p.Ala44_Leu49del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,595,104 control chromosomes in the GnomAD database, including 237 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V36V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.020 (120 hom., cov: 0)
  • Exomes 𝑓: 0.0025 (117 hom.)
• Consequence: SMPD1 NM_000543.5 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 11-6390705-TGCTGGCGCTGGCGCTGGC-T is Benign according to our data. Variant chr11-6390705-TGCTGGCGCTGGCGCTGGC-T is described in ClinVar as [Benign]. Clinvar id is 281329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6390705-TGCTGGCGCTGGCGCTGGC-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.126_143del	p.Ala44_Leu49del	inframe_deletion	1/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.126_143del	p.Ala44_Leu49del	inframe_deletion	1/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 2974 AN: 147220 Hom.: 120 Cov.: 0

Gnomad AFR AF: 0.0697

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00627

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000399

Gnomad SAS AF: 0.000647

Gnomad FIN AF: 0.000296

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000728

Gnomad OTH AF: 0.0149

GnomAD3 exomes AF: 0.00592 AC: 1415 AN: 238972 Hom.: 62 AF XY: 0.00446 AC XY: 582 AN XY: 130606

Gnomad AFR exome AF: 0.0818

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000454

Gnomad SAS exome AF: 0.000729

Gnomad FIN exome AF: 0.000293

Gnomad NFE exome AF: 0.000859

Gnomad OTH exome AF: 0.00275

GnomAD4 exome AF: 0.00253 AC: 3656 AN: 1447758 Hom.: 117 AF XY: 0.00218 AC XY: 1569 AN XY: 720014

Gnomad4 AFR exome AF: 0.0719

Gnomad4 AMR exome AF: 0.00372

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.000726

Gnomad4 FIN exome AF: 0.000212

Gnomad4 NFE exome AF: 0.000656

Gnomad4 OTH exome AF: 0.00481

GnomAD4 genome AF: 0.0202 AC: 2977 AN: 147346 Hom.: 120 Cov.: 0 AF XY: 0.0198 AC XY: 1424 AN XY: 71994

Gnomad4 AFR AF: 0.0696

Gnomad4 AMR AF: 0.00632

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000400

Gnomad4 SAS AF: 0.000646

Gnomad4 FIN AF: 0.000296

Gnomad4 NFE AF: 0.000728

Gnomad4 OTH AF: 0.0147

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2018	Variant summary: SMPD1 c.126_143del18 (p.Ala44_Leu49del) results in an in-frame deletion that is predicted to remove 6 amino acids from the encoded protein. The variant allele was found at a frequency of 0.0069 in 110368 control chromosomes in the ExAC database, including 43 homozygotes. The observed variant frequency is approximately 3.071 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type A phenotype (0.0022), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.126_143del18 in individuals affected with Niemann-Pick Disease Type A and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2019	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2017	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Niemann-Pick disease, type A Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 09, 2017

- -

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;