rs797044799

Variant names:

• chr11-6391939-C-A
• rs797044799
• NM_000543.5:c.874C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-6391939-C-A
• chr11-6391939-C-G
• chr11-6391939-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000543.5(SMPD1):​c.874C>A​(p.Gln292Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.103
• Publications: 20 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 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000543.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19467503).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.874C>A	p.Gln292Lys	missense_variant	Exon 2 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.874C>A	p.Gln292Lys	missense_variant	Exon 2 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Sphingomyelin/cholesterol lipidosis Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Associated with intermediate phenotypes with later-onset neuronopathic disease. Appears to be relatively common in persons of Czech & Slovak heritage. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	9.0
DANN	Benign	0.86
DEOGEN2	Uncertain	0.68	D;T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.36	T
PhyloP100		-0.10
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.30	T;T;T
Vest4		0.12
MVP		0.97
MPC		0.27
ClinPred		0.022	T
GERP RS		1.7
PromoterAI		0.00030	Neutral
Varity_R		0.46
gMVP		0.79
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs797044799; hg19: chr11-6413169;