11-6392136-C-T

Variant names:

• chr11-6392136-C-T
• rs72896268
• NM_000543.5:c.1071C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 2P and 14B. PM1 BP4_Moderate BP6_Very_Strong BS2

The NM_001318088.2(SMPD1):​c.110C>T​(p.Pro37Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00756 in 1,614,104 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/7 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P37R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0056 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0078 (50 hom.)
• Consequence: SMPD1 NM_001318088.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.296
• Publications: 3 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: Genomics England PanelApp, Orphanet, G2P
• Niemann-Pick disease type B

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 4 uncertain in NM_001318088.2
• BP4: Computational evidence support a benign effect (REVEL=0.028).
• BP6: Variant 11-6392136-C-T is Benign according to our data. Variant chr11-6392136-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318088.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD1	NM_000543.5	MANE Select	c.1071C>T	p.Ala357Ala	synonymous	Exon 2 of 6	NP_000534.3
	SMPD1	NM_001318088.2		c.110C>T	p.Pro37Leu	missense	Exon 2 of 6	NP_001305017.1
	SMPD1	NM_001007593.3		c.1068C>T	p.Ala356Ala	synonymous	Exon 2 of 6	NP_001007594.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.1071C>T	p.Ala357Ala	synonymous	Exon 2 of 6	ENSP00000340409.4
	SMPD1	ENST00000526280.1	TSL:1	c.258C>T	p.Ala86Ala	synonymous	Exon 1 of 4	ENSP00000436278.1
	SMPD1	ENST00000533123.5	TSL:1	n.1071C>T		non_coding_transcript_exon	Exon 2 of 5	ENSP00000435950.1

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 855 AN: 152108 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00922

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00513 AC: 1287 AN: 250744 AF XY: 0.00543

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00807

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00777 AC: 11355 AN: 1461878 Hom.: 50 Cov.: 36 AF XY: 0.00757 AC XY: 5504 AN XY: 727242

African (AFR) AF: 0.00119 AC: 40 AN: 33480

American (AMR) AF: 0.00356 AC: 159 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 278 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00227 AC: 196 AN: 86254

European-Finnish (FIN) AF: 0.00112 AC: 60 AN: 53418

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.00913 AC: 10155 AN: 1112002

Other (OTH) AF: 0.00714 AC: 431 AN: 60396

GnomAD4 genome AF: 0.00562 AC: 855 AN: 152226 Hom.: 3 Cov.: 31 AF XY: 0.00516 AC XY: 384 AN XY: 74418

African (AFR) AF: 0.00176 AC: 73 AN: 41524

American (AMR) AF: 0.00503 AC: 77 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00920 AC: 626 AN: 68012

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00708 Hom.: 4

Bravo AF: 0.00566

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.00919

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	3	Niemann-Pick disease, type A (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)
-	-	1	Sphingomyelin/cholesterol lipidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.8
DANN	Benign	0.85
PhyloP100		-0.30
PromoterAI		0.0020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs72896268; hg19: chr11-6413366; COSMIC: COSV108805025; COSMIC: COSV108805025;