chr11-6390700-CCTGGTG-C

Variant names:

• chr11-6390700-CCTGGTG-C
• rs775860642
• NM_000543.5:c.107_112delTGCTGG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_000543.5(SMPD1):​c.107_112delTGCTGG​(p.Val36_Leu37del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,546,720 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V36V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0018 (16 hom.)
• Consequence: SMPD1 NM_000543.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.67
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000543.5
• BP6: Variant 11-6390700-CCTGGTG-C is Benign according to our data. Variant chr11-6390700-CCTGGTG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256590.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

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_112delTGCTGG	p.Val36_Leu37del	disruptive_inframe_deletion	Exon 1 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.107_112delTGCTGG	p.Val36_Leu37del	disruptive_inframe_deletion	Exon 1 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.107_112delTGCTGG	p.Val36_Leu37del	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_112delTGCTGG	p.Val36_Leu37del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000531303.5	TSL:1	n.107_112delTGCTGG		non_coding_transcript_exon	Exon 1 of 6	ENSP00000432625.1	E9PPK6
	SMPD1	ENST00000533123.5	TSL:1	n.107_112delTGCTGG		non_coding_transcript_exon	Exon 1 of 5	ENSP00000435950.1	G3V1E1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 196 AN: 139132 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000742

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00126

Gnomad ASJ AF: 0.000892

Gnomad EAS AF: 0.00312

Gnomad SAS AF: 0.00369

Gnomad FIN AF: 0.00168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00211

GnomAD2 exomes AF: 0.00264 AC: 613 AN: 232506 AF XY: 0.00269

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.000309

Gnomad EAS exome AF: 0.00332

Gnomad FIN exome AF: 0.00292

Gnomad NFE exome AF: 0.00271

Gnomad OTH exome AF: 0.00193

GnomAD4 exome AF: 0.00183 AC: 2572 AN: 1407484 Hom.: 16 AF XY: 0.00188 AC XY: 1318 AN XY: 700306

African (AFR) AF: 0.000695 AC: 23 AN: 33114

American (AMR) AF: 0.00209 AC: 90 AN: 43044

Ashkenazi Jewish (ASJ) AF: 0.000158 AC: 4 AN: 25306

East Asian (EAS) AF: 0.00220 AC: 79 AN: 35856

South Asian (SAS) AF: 0.00371 AC: 306 AN: 82498

European-Finnish (FIN) AF: 0.00297 AC: 148 AN: 49770

Middle Eastern (MID) AF: 0.00214 AC: 12 AN: 5608

European-Non Finnish (NFE) AF: 0.00166 AC: 1782 AN: 1074246

Other (OTH) AF: 0.00221 AC: 128 AN: 58042

GnomAD4 genome AF: 0.00141 AC: 196 AN: 139236 Hom.: 0 Cov.: 0 AF XY: 0.00165 AC XY: 112 AN XY: 67720

African (AFR) AF: 0.000739 AC: 28 AN: 37864

American (AMR) AF: 0.00126 AC: 18 AN: 14326

Ashkenazi Jewish (ASJ) AF: 0.000892 AC: 3 AN: 3362

East Asian (EAS) AF: 0.00312 AC: 15 AN: 4804

South Asian (SAS) AF: 0.00369 AC: 15 AN: 4062

European-Finnish (FIN) AF: 0.00168 AC: 15 AN: 8952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.00156 AC: 98 AN: 62990

Other (OTH) AF: 0.00208 AC: 4 AN: 1920

Alfa AF: 0.00178 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Niemann-Pick disease, type A (1)
-	-	1	Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)
-	-	1	not specified (1)
-	-	1	SMPD1-related disorder (1)
-	1	-	Sphingomyelin/cholesterol lipidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=199/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs775860642; hg19: chr11-6411930; COSMIC: COSV54969884; COSMIC: COSV54969884;