chr11-6391815-C-A

Position:

• chr11-6391815-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP5_Moderate

The NM_000543.5(SMPD1):​c.750C>A​(p.Ser250Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S250N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SMPD1 NM_000543.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.77

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_000543.5 (SMPD1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 371576
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr11-6391814-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2939476.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 11-6391815-C-A is Pathogenic according to our data. Variant chr11-6391815-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-6391815-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPD1	NM_000543.5	c.750C>A	p.Ser250Arg	missense_variant	2/6	ENST00000342245.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPD1	ENST00000342245.9	c.750C>A	p.Ser250Arg	missense_variant	2/6	1	NM_000543.5	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Niemann-Pick disease, type A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Sep 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	20
DANN	Benign	0.94
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	-0.19	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.65	N;N
REVEL	Uncertain	0.48
Sift	Benign	1.0	T;T
Sift4G	Benign	0.78	T;T
Vest4		0.91
MVP		0.98
MPC		0.31
ClinPred		0.47	T
GERP RS		5.0
Varity_R		0.28
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs1423504237; hg19: chr11-6413045;