rs1050228

Variant names:

• chr11-6390705-T-C
• rs1050228
• NM_000543.5:c.107T>C
• SMPD1 p.Val36Ala

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000543.5(SMPD1):​c.107T>C​(p.Val36Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 149,950 control chromosomes in the GnomAD database, including 21,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V36L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.49 (21996 hom., cov: 27)
  • Exomes 𝑓: 0.52 (204749 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.59
• Publications: 46 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, G2P, PanelApp Australia, Genomics England PanelApp
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1145776E-6).
• BP6: Variant 11-6390705-T-C is Benign according to our data. Variant chr11-6390705-T-C is described in ClinVar as Benign. ClinVar VariationId is 93311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.769 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.107T>C	p.Val36Ala	missense	Exon 1 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.107T>C	p.Val36Ala	missense	Exon 1 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.107T>C	p.Val36Ala	missense	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.107T>C	p.Val36Ala	missense	Exon 1 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000531303.5	TSL:1	n.107T>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000432625.1	E9PPK6
	SMPD1	ENST00000533123.5	TSL:1	n.107T>C		non_coding_transcript_exon	Exon 1 of 5	ENSP00000435950.1	G3V1E1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 73273 AN: 149830 Hom.: 21993 Cov.: 27

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.509

GnomAD2 exomes AF: 0.554 AC: 132344 AN: 238972 AF XY: 0.552

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.729

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.768

Gnomad FIN exome AF: 0.541

Gnomad NFE exome AF: 0.507

Gnomad OTH exome AF: 0.548

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.520 AC: 752397 AN: 1447526 Hom.: 204749 Cov.: 70 AF XY: 0.523 AC XY: 376272 AN XY: 719874

African (AFR) AF: 0.220 AC: 7295 AN: 33142

American (AMR) AF: 0.726 AC: 32196 AN: 44324

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 14759 AN: 25804

East Asian (EAS) AF: 0.790 AC: 31211 AN: 39502

South Asian (SAS) AF: 0.572 AC: 48843 AN: 85428

European-Finnish (FIN) AF: 0.557 AC: 28774 AN: 51700

Middle Eastern (MID) AF: 0.569 AC: 3239 AN: 5692

European-Non Finnish (NFE) AF: 0.503 AC: 554602 AN: 1102276

Other (OTH) AF: 0.528 AC: 31478 AN: 59658

GnomAD4 genome AF: 0.489 AC: 73292 AN: 149950 Hom.: 21996 Cov.: 27 AF XY: 0.498 AC XY: 36458 AN XY: 73276

African (AFR) AF: 0.254 AC: 10365 AN: 40844

American (AMR) AF: 0.662 AC: 10038 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2069 AN: 3434

East Asian (EAS) AF: 0.789 AC: 3994 AN: 5060

South Asian (SAS) AF: 0.616 AC: 2920 AN: 4740

European-Finnish (FIN) AF: 0.565 AC: 5863 AN: 10372

Middle Eastern (MID) AF: 0.540 AC: 149 AN: 276

European-Non Finnish (NFE) AF: 0.543 AC: 36453 AN: 67076

Other (OTH) AF: 0.511 AC: 1063 AN: 2080

Alfa AF: 0.503 Hom.: 2157

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Niemann-Pick disease, type A (3)
-	-	2	not specified (2)
-	-	1	Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)
-	-	1	Niemann-Pick disease, type B (1)
-	-	1	SMPD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.8
DANN	Benign	0.61
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.032
Sift	Benign	0.29	T
Sift4G	Benign	0.58	T
PromoterAI		0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.031
gMVP		0.59
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1050228;

hg19: chr11-6411935;

COSMIC: COSV54967594;

COSMIC: COSV54967594;