11-6393961-A-G

Variant names:

• chr11-6393961-A-G
• rs267607074
• NM_000543.5:c.1406A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000543.5(SMPD1):​c.1406A>G​(p.Tyr469Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y469S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.88
• Publications: 5 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000543.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-6393961-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 11-6393961-A-G is Pathogenic according to our data. Variant chr11-6393961-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 992707.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD1	NM_000543.5	MANE Select	c.1406A>G	p.Tyr469Cys	missense	Exon 5 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.1403A>G	p.Tyr468Cys	missense	Exon 5 of 6	NP_001007594.2
	SMPD1	NM_001365135.2		c.1274A>G	p.Tyr425Cys	missense	Exon 4 of 5	NP_001352064.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.1406A>G	p.Tyr469Cys	missense	Exon 5 of 6	ENSP00000340409.4
	SMPD1	ENST00000526280.1	TSL:1	c.461A>G	p.Tyr154Cys	missense	Exon 3 of 4	ENSP00000436278.1
	SMPD1	ENST00000531303.5	TSL:1	n.*237A>G		non_coding_transcript_exon	Exon 5 of 6	ENSP00000432625.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:2

Dec 30, 2020

Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 469 of the SMPD1 protein (p.Tyr469Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Niemann-Pick disease (PMID: 33675270). ClinVar contains an entry for this variant (Variation ID: 992707). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMPD1 protein function. This variant disrupts the p.Tyr469 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19405096, 30795770). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Niemann-Pick disease, type B Pathogenic:1

Nov 27, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.93 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000992707 /PMID: 33675270). A different missense change at the same codon (p.Tyr469Ser) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002996 /PMID: 19405096). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Sphingomyelin/cholesterol lipidosis Pathogenic:1

Jul 31, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SMPD1 c.1406A>G (p.Tyr469Cys) results in a non-conservative amino acid change located in the metallophosphatase domain (IPR041805) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251494 control chromosomes (gnomAD). c.1406A>G has been observed in individuals affected with Niemann-Pick Disease (Hu_2021). A different variant affecting the same codon has been classified as pathogenic by our lab (c.1406A>C, p.Tyr469Ser), supporting the critical relevance of codon 469 to SMPD1 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33675270). ClinVar contains an entry for this variant (Variation ID: 992707). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		6.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.94
MVP		0.99
MPC		0.90
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.84
gMVP		0.94
Mutation Taster		=12/88	disease causing (ClinVar)

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: rs267607074; hg19: chr11-6415191;