11-6394267-A-T

Variant names:

• chr11-6394267-A-T
• rs371837210
• NM_000543.5:c.1556A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000543.5(SMPD1):​c.1556A>T​(p.Tyr519Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y519C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.05
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 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 chr11-6394267-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437453.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30795538).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.1556A>T	p.Tyr519Phe	missense_variant	Exon 6 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.1556A>T	p.Tyr519Phe	missense_variant	Exon 6 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461880 Hom.: 0 Cov.: 34 AF XY: 0.0000234 AC XY: 17 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 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: 0.0000270 AC: 30 AN: 1112000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SMPD1-related disorder Uncertain:1

Jan 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SMPD1 c.1556A>T variant is predicted to result in the amino acid substitution p.Tyr519Phe. To our knowledge, this variant has not been reported in the literature. Although an alternate variant at the same amino acid position has been associated with autosomal recessive SMPD1-related disease, the Tyr519Phe change is documented in 31 heterozygous individuals in gnomAD version 4 data, and has not been reported in any affected individuals (Ricci et al. 2004. PubMed ID: 15221801). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	15
DANN	Benign	0.93
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	0.41	D
PhyloP100		2.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.50
Sift	Benign	0.19	T;T
Sift4G	Benign	0.18	T;T
Vest4		0.24
MVP		0.93
MPC		0.22
ClinPred		0.27	T
GERP RS		3.6
Varity_R		0.28
gMVP		0.69
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs371837210; hg19: chr11-6415497;