11-6391624-C-G

Variant names:

• chr11-6391624-C-G
• rs74053349
• NM_000543.5:c.559C>G

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.559C>G​(p.Pro187Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,373,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P187S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.759
• Publications: 0 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000543.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24380314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.559C>G	p.Pro187Ala	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.559C>G	p.Pro187Ala	missense_variant	Exon 2 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000437 AC: 6 AN: 1373792 Hom.: 0 Cov.: 33 AF XY: 0.00000442 AC XY: 3 AN XY: 679260

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000320 AC: 1 AN: 31240

American (AMR) AF: 0.00 AC: 0 AN: 36164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25058

East Asian (EAS) AF: 0.00 AC: 0 AN: 35822

South Asian (SAS) AF: 0.00 AC: 0 AN: 78998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4154

European-Non Finnish (NFE) AF: 0.00000378 AC: 4 AN: 1059530

Other (OTH) AF: 0.0000175 AC: 1 AN: 57036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	2.4
DANN	Benign	0.72
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	0.10	D
PhyloP100		0.76
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Benign	0.20
Sift	Benign	0.086	T;T
Sift4G	Benign	0.15	T;T
Vest4		0.21
MVP		0.96
MPC		0.25
ClinPred		0.21	T
GERP RS		-0.45
PromoterAI		0.020	Neutral
Varity_R		0.11
gMVP		0.72
Mutation Taster		=97/3	polymorphism

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: rs74053349; hg19: chr11-6412854;