rs1050233

Variant names:

• chr11-6392036-C-T
• rs1050233
• NM_000543.5:c.971C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000543.5(SMPD1):​c.971C>T​(p.Thr324Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.83
• 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, G2P
• Niemann-Pick disease type B

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000543.5
• PM2: Very rare variant in population databases, with high coverage

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.971C>T	p.Thr324Ile	missense	Exon 2 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.968C>T	p.Thr323Ile	missense	Exon 2 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.971C>T	p.Thr324Ile	missense	Exon 2 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.971C>T	p.Thr324Ile	missense	Exon 2 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000526280.1	TSL:1	c.158C>T	p.Thr53Ile	missense	Exon 1 of 4	ENSP00000436278.1	H0YEP5
	SMPD1	ENST00000533123.5	TSL:1	n.971C>T		non_coding_transcript_exon	Exon 2 of 5	ENSP00000435950.1	G3V1E1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.44	D
PhyloP100		3.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.58
Sift	Benign	0.21	T
Sift4G	Uncertain	0.012	D
Vest4		0.62
MVP		0.97
MPC		0.32
ClinPred		0.74	D
GERP RS		4.0
PromoterAI		0.052	Neutral
Varity_R		0.23
gMVP		0.91
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1050233; hg19: chr11-6413266;