chr11-6394272-C-T

Variant names:

• chr11-6394272-C-T
• rs147258619
• NM_000543.5:c.1561C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_000543.5(SMPD1):​c.1561C>T​(p.Leu521Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000587 in 1,614,230 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L521L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: SMPD1 NM_000543.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.46
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 11-6394272-C-T is Benign according to our data. Variant chr11-6394272-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289949.
• BP7: Synonymous conserved (PhyloP=2.46 with no splicing effect.
• 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.1561C>T	p.Leu521Leu	synonymous	Exon 6 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.1558C>T	p.Leu520Leu	synonymous	Exon 6 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.1429C>T	p.Leu477Leu	synonymous	Exon 5 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.1561C>T	p.Leu521Leu	synonymous	Exon 6 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000526280.1	TSL:1	c.616C>T	p.Leu206Leu	synonymous	Exon 4 of 4	ENSP00000436278.1	H0YEP5
	SMPD1	ENST00000531303.5	TSL:1	n.*412C>T		non_coding_transcript_exon	Exon 6 of 6	ENSP00000432625.1	E9PPK6

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 479 AN: 152226 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000792 AC: 199 AN: 251340 AF XY: 0.000545

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000321 AC: 469 AN: 1461886 Hom.: 2 Cov.: 34 AF XY: 0.000265 AC XY: 193 AN XY: 727244

African (AFR) AF: 0.0114 AC: 381 AN: 33480

American (AMR) AF: 0.000760 AC: 34 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112004

Other (OTH) AF: 0.000811 AC: 49 AN: 60396

GnomAD4 genome AF: 0.00314 AC: 479 AN: 152344 Hom.: 1 Cov.: 33 AF XY: 0.00338 AC XY: 252 AN XY: 74504

African (AFR) AF: 0.0108 AC: 447 AN: 41576

American (AMR) AF: 0.00157 AC: 24 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00134 Hom.: 1

Bravo AF: 0.00360

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Niemann-Pick disease, type A (2)
-	-	1	Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)
-	-	1	not specified (1)
-	-	1	SMPD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.1
DANN	Benign	0.71
PhyloP100		2.5
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs147258619; hg19: chr11-6415502;