Genetic Variant NM_000543.5:c.10T>C (chr11-6390608-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000543.5(SMPD1):c.10T>C(p.Tyr4His) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

SMPD1
NM_000543.5 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.607

Publications

0 publications found

Variant links:

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: Orphanet, Genomics England PanelApp, PanelApp Australia, G2P
Niemann-Pick disease type B
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

SMPD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036748618).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMPD1	NM_000543.5	MANE Select	c.10T>C	p.Tyr4His	missense	Exon 1 of 6	NP_000534.3
SMPD1	NM_001007593.3		c.10T>C	p.Tyr4His	missense	Exon 1 of 6	NP_001007594.2	P17405-4
SMPD1	NM_001365135.2		c.10T>C	p.Tyr4His	missense	Exon 1 of 5	NP_001352064.1	P17405-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.10T>C	p.Tyr4His	missense	Exon 1 of 6	ENSP00000340409.4	P17405-1
SMPD1	ENST00000531303.5	TSL:1	n.10T>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000432625.1	E9PPK6
SMPD1	ENST00000533123.5	TSL:1	n.10T>C		non_coding_transcript_exon	Exon 1 of 5	ENSP00000435950.1	G3V1E1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Sphingomyelin/cholesterol lipidosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.79

CADD

Benign

8.6

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.28

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0063

LIST_S2

Benign

0.34

M_CAP

Benign

0.0024

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.97

PhyloP100

0.61

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.45

REVEL

Benign

0.032

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.044

MutPred

0.21

Loss of catalytic residue at Y4 (P = 0.0218)

MVP

0.43

MPC

0.27

ClinPred

0.023

GERP RS

1.8

PromoterAI

0.0031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.040

gMVP

0.40

Mutation Taster

=94/6

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over