11-6390724-GCTGGCGCTGGCGCTGGCT-GCTGGCGCTGGCGCTGGCTCTGGCGCTGGCGCTGGCT

Variant names:

• chr11-6390724-G-GCTGGCGCTGGCGCTGGCT
• rs1554933850
• NM_000543.5:c.130_147dupGCGCTGGCGCTGGCTCTG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_000543.5(SMPD1):​c.130_147dupGCGCTGGCGCTGGCTCTG​(p.Ala44_Leu49dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,426,694 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. S50S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMPD1 NM_000543.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.325
• Publications: 0 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: Genomics England PanelApp, Orphanet, G2P
• Niemann-Pick disease type B

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000543.5

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.130_147dupGCGCTGGCGCTGGCTCTG	p.Ala44_Leu49dup	conservative_inframe_insertion	Exon 1 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.130_147dupGCGCTGGCGCTGGCTCTG	p.Ala44_Leu49dup	conservative_inframe_insertion	Exon 1 of 6	NP_001007594.2
	SMPD1	NM_001365135.2		c.130_147dupGCGCTGGCGCTGGCTCTG	p.Ala44_Leu49dup	conservative_inframe_insertion	Exon 1 of 5	NP_001352064.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.130_147dupGCGCTGGCGCTGGCTCTG	p.Ala44_Leu49dup	conservative_inframe_insertion	Exon 1 of 6	ENSP00000340409.4
	SMPD1	ENST00000531303.5	TSL:1	n.130_147dupGCGCTGGCGCTGGCTCTG		non_coding_transcript_exon	Exon 1 of 6	ENSP00000432625.1
	SMPD1	ENST00000533123.5	TSL:1	n.130_147dupGCGCTGGCGCTGGCTCTG		non_coding_transcript_exon	Exon 1 of 5	ENSP00000435950.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426694 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 708184

African (AFR) AF: 0.00 AC: 0 AN: 30394

American (AMR) AF: 0.00 AC: 0 AN: 42518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25350

East Asian (EAS) AF: 0.00 AC: 0 AN: 38484

South Asian (SAS) AF: 0.00 AC: 0 AN: 79626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5588

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1094466

Other (OTH) AF: 0.0000170 AC: 1 AN: 58694

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Niemann-Pick disease, type A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33

Splicing

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

Other links and lift over

dbSNP: rs1554933850; hg19: chr11-6411954;