rs116480929

Variant names:

• chr11-6393700-C-T
• rs116480929
• NM_000543.5:c.1340+7C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000543.5(SMPD1):​c.1340+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,611,760 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: SMPD1 NM_000543.5 splice_region, intron
• Scores: Splicing: ADA: 0.0002955
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.714
• 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: 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-6393700-C-T is Benign according to our data. Variant chr11-6393700-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.1340+7C>T		splice_region intron	N/A	NP_000534.3
	SMPD1	NM_001007593.3		c.1337+7C>T		splice_region intron	N/A	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.1208+7C>T		splice_region intron	N/A	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.1340+7C>T		splice_region intron	N/A	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000526280.1	TSL:1	c.395+7C>T		splice_region intron	N/A	ENSP00000436278.1	H0YEP5
	SMPD1	ENST00000531303.5	TSL:1	n.*171+7C>T		splice_region intron	N/A	ENSP00000432625.1	E9PPK6

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152052 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000341 AC: 85 AN: 248948 AF XY: 0.000208

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000209 AC: 305 AN: 1459590 Hom.: 2 Cov.: 30 AF XY: 0.000186 AC XY: 135 AN XY: 726344

African (AFR) AF: 0.00449 AC: 150 AN: 33444

American (AMR) AF: 0.0000894 AC: 4 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00151 AC: 60 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000496 AC: 55 AN: 1109894

Other (OTH) AF: 0.000514 AC: 31 AN: 60324

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152170 Hom.: 1 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74380

African (AFR) AF: 0.00455 AC: 189 AN: 41516

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000663 Hom.: 0

Bravo AF: 0.00142

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.0
DANN	Benign	0.79
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs116480929; hg19: chr11-6414930;