rs550365194

Variant names:

• chr11-6390700-CCTGGTGCTGGCG-C
• rs550365194
• NM_000543.5:c.107_118delTGCTGGCGCTGG

Your query was ambiguous. Multiple possible variants found:

• chr11-6390700-CCTGGTGCTGGCG-C
• chr11-6390700-CCTGGTGCTGGCG-CCTGGTGCTGGCGCTGGTGCTGGCG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_000543.5(SMPD1):​c.107_118delTGCTGGCGCTGG​(p.Val36_Leu39del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0753 in 1,546,630 control chromosomes in the GnomAD database, including 4,521 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V36V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.063 (331 hom., cov: 0)
  • Exomes 𝑓: 0.076 (4190 hom.)
• Consequence: SMPD1 NM_000543.5 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.67
• Publications: 7 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: Orphanet, Genomics England PanelApp, PanelApp Australia, G2P
• Niemann-Pick disease type B

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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000543.5
• BP6: Variant 11-6390700-CCTGGTGCTGGCG-C is Benign according to our data. Variant chr11-6390700-CCTGGTGCTGGCG-C is described in ClinVar as Benign. ClinVar VariationId is 193113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0821 is higher than 0.05.

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.107_118delTGCTGGCGCTGG	p.Val36_Leu39del	disruptive_inframe_deletion	Exon 1 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.107_118delTGCTGGCGCTGG	p.Val36_Leu39del	disruptive_inframe_deletion	Exon 1 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.107_118delTGCTGGCGCTGG	p.Val36_Leu39del	disruptive_inframe_deletion	Exon 1 of 5	NP_001352064.1	P17405-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.107_118delTGCTGGCGCTGG	p.Val36_Leu39del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000531303.5	TSL:1	n.107_118delTGCTGGCGCTGG		non_coding_transcript_exon	Exon 1 of 6	ENSP00000432625.1	E9PPK6
	SMPD1	ENST00000533123.5	TSL:1	n.107_118delTGCTGGCGCTGG		non_coding_transcript_exon	Exon 1 of 5	ENSP00000435950.1	G3V1E1

Frequencies

GnomAD3 genomes AF: 0.0631 AC: 8772 AN: 139088 Hom.: 332 Cov.: 0

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.0443

Gnomad AMR AF: 0.0493

Gnomad ASJ AF: 0.0877

Gnomad EAS AF: 0.0680

Gnomad SAS AF: 0.0780

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0971

Gnomad NFE AF: 0.0840

Gnomad OTH AF: 0.0717

GnomAD2 exomes AF: 0.0703 AC: 16351 AN: 232506 AF XY: 0.0722

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.0367

Gnomad ASJ exome AF: 0.0920

Gnomad EAS exome AF: 0.0691

Gnomad FIN exome AF: 0.0981

Gnomad NFE exome AF: 0.0820

Gnomad OTH exome AF: 0.0732

GnomAD4 exome AF: 0.0765 AC: 107636 AN: 1407438 Hom.: 4190 AF XY: 0.0764 AC XY: 53525 AN XY: 700294

African (AFR) AF: 0.0144 AC: 476 AN: 33120

American (AMR) AF: 0.0389 AC: 1675 AN: 43040

Ashkenazi Jewish (ASJ) AF: 0.0934 AC: 2363 AN: 25308

East Asian (EAS) AF: 0.0632 AC: 2265 AN: 35850

South Asian (SAS) AF: 0.0678 AC: 5590 AN: 82494

European-Finnish (FIN) AF: 0.0960 AC: 4777 AN: 49768

Middle Eastern (MID) AF: 0.0827 AC: 464 AN: 5608

European-Non Finnish (NFE) AF: 0.0799 AC: 85799 AN: 1074212

Other (OTH) AF: 0.0728 AC: 4227 AN: 58038

GnomAD4 genome AF: 0.0630 AC: 8773 AN: 139192 Hom.: 331 Cov.: 0 AF XY: 0.0630 AC XY: 4263 AN XY: 67702

African (AFR) AF: 0.0185 AC: 699 AN: 37864

American (AMR) AF: 0.0492 AC: 704 AN: 14320

Ashkenazi Jewish (ASJ) AF: 0.0877 AC: 295 AN: 3362

East Asian (EAS) AF: 0.0683 AC: 328 AN: 4802

South Asian (SAS) AF: 0.0776 AC: 315 AN: 4060

European-Finnish (FIN) AF: 0.106 AC: 945 AN: 8948

Middle Eastern (MID) AF: 0.102 AC: 26 AN: 256

European-Non Finnish (NFE) AF: 0.0840 AC: 5290 AN: 62962

Other (OTH) AF: 0.0730 AC: 140 AN: 1918

Alfa AF: 0.0430 Hom.: 38

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	1	Niemann-Pick disease, type A (1)
-	-	1	Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=198/2	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs550365194; hg19: chr11-6411930; COSMIC: COSV54966432; COSMIC: COSV54966432;