11-6390705-TGCTGGCGCTGGCGCTGGCGCTGGC-TGCTGGC

Variant names:

• chr11-6390705-TGCTGGCGCTGGCGCTGGC-T
• rs3838786
• NM_000543.5:c.126_143delGCTGGCGCTGGCGCTGGC

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM1 BP3 BP6_Very_Strong BA1

The NM_000543.5(SMPD1):​c.126_143delGCTGGCGCTGGCGCTGGC​(p.Leu43_Ala48del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,595,104 control chromosomes in the GnomAD database, including 237 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. A42A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (120 hom., cov: 0)
  • Exomes 𝑓: 0.0025 (117 hom.)
• Consequence: SMPD1 NM_000543.5 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.65
• Publications: 17 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 -15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_000543.5
• BP3: Nonframeshift variant in repetitive region in NM_000543.5
• BP6: Variant 11-6390705-TGCTGGCGCTGGCGCTGGC-T is Benign according to our data. Variant chr11-6390705-TGCTGGCGCTGGCGCTGGC-T is described in ClinVar as Benign. ClinVar VariationId is 281329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0674 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.126_143delGCTGGCGCTGGCGCTGGC	p.Leu43_Ala48del	disruptive_inframe_deletion	Exon 1 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.126_143delGCTGGCGCTGGCGCTGGC	p.Leu43_Ala48del	disruptive_inframe_deletion	Exon 1 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.126_143delGCTGGCGCTGGCGCTGGC	p.Leu43_Ala48del	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.126_143delGCTGGCGCTGGCGCTGGC	p.Leu43_Ala48del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000531303.5	TSL:1	n.126_143delGCTGGCGCTGGCGCTGGC		non_coding_transcript_exon	Exon 1 of 6	ENSP00000432625.1	E9PPK6
	SMPD1	ENST00000533123.5	TSL:1	n.126_143delGCTGGCGCTGGCGCTGGC		non_coding_transcript_exon	Exon 1 of 5	ENSP00000435950.1	G3V1E1

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

GnomAD2 exomes AF: 0.00592 AC: 1415 AN: 238972 AF XY: 0.00446

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 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

African (AFR) AF: 0.0719 AC: 2383 AN: 33148

American (AMR) AF: 0.00372 AC: 165 AN: 44336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25808

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39504

South Asian (SAS) AF: 0.000726 AC: 62 AN: 85446

European-Finnish (FIN) AF: 0.000212 AC: 11 AN: 51776

Middle Eastern (MID) AF: 0.00316 AC: 18 AN: 5692

European-Non Finnish (NFE) AF: 0.000656 AC: 723 AN: 1102378

Other (OTH) AF: 0.00481 AC: 287 AN: 59670

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

African (AFR) AF: 0.0696 AC: 2797 AN: 40208

American (AMR) AF: 0.00632 AC: 94 AN: 14864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3374

East Asian (EAS) AF: 0.000400 AC: 2 AN: 5004

South Asian (SAS) AF: 0.000646 AC: 3 AN: 4642

European-Finnish (FIN) AF: 0.000296 AC: 3 AN: 10138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.000728 AC: 48 AN: 65924

Other (OTH) AF: 0.0147 AC: 30 AN: 2042

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	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		2.7
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: rs3838786; hg19: chr11-6411935;