rs550067660

Positions:

• chr11-6390700-CCTGGTGCTGGCGCTGGCGCTGGCG-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000543.5(SMPD1):​c.107_130del​(p.Val36_Leu43del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,546,828 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (13 hom.)
• Consequence: SMPD1 NM_000543.5 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.67

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 -12 ACMG points.

• BP6: Variant 11-6390700-CCTGGTGCTGGCGCTGGCGCTGGCG-C is Benign according to our data. Variant chr11-6390700-CCTGGTGCTGGCGCTGGCGCTGGCG-C is described in ClinVar as [Likely_benign]. Clinvar id is 459633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.107_130del	p.Val36_Leu43del	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.107_130del	p.Val36_Leu43del	inframe_deletion	1/6	1	NM_000543.5	ENSP00000340409	P3

Frequencies

GnomAD3 genomes AF: 0.000970 AC: 135 AN: 139132 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000909

Gnomad ASJ AF: 0.00387

Gnomad EAS AF: 0.000415

Gnomad SAS AF: 0.00713

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00719

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.000527

GnomAD3 exomes AF: 0.00188 AC: 437 AN: 232506 Hom.: 3 AF XY: 0.00202 AC XY: 256 AN XY: 126968

Gnomad AFR exome AF: 0.000485

Gnomad AMR exome AF: 0.00155

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.000466

Gnomad SAS exome AF: 0.00725

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.00127 AC: 1792 AN: 1407592 Hom.: 13 AF XY: 0.00147 AC XY: 1032 AN XY: 700352

Gnomad4 AFR exome AF: 0.000483

Gnomad4 AMR exome AF: 0.00144

Gnomad4 ASJ exome AF: 0.00383

Gnomad4 EAS exome AF: 0.000446

Gnomad4 SAS exome AF: 0.00713

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000822

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.000977 AC: 136 AN: 139236 Hom.: 0 Cov.: 0 AF XY: 0.00102 AC XY: 69 AN XY: 67722

Gnomad4 AFR AF: 0.000158

Gnomad4 AMR AF: 0.000907

Gnomad4 ASJ AF: 0.00387

Gnomad4 EAS AF: 0.000416

Gnomad4 SAS AF: 0.00739

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.000521

Alfa AF: 0.00169 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SMPD1: PM4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

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: rs550067660; hg19: chr11-6411930;