dbSNP rs764411535: SPTLC3:p.Met202Ile (chr20-13074496-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_018327.4(SPTLC3):c.606G>A(p.Met202Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,457,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SPTLC3
NM_018327.4 missense, splice_region

Scores

Splicing: ADA: 0.0003045

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.09

Publications

0 publications found

Variant links:

Genes affected

SPTLC3 (HGNC:16253): (serine palmitoyltransferase long chain base subunit 3) This gene encodes a subunit of the serine palmitoyltransferase complex which catalyzes the rate-limiting step in sphingolipid biosynthesis. This subunit metabolizes lauroyl- and myristoyl-CoA and generates C14 and C16-sphingoid bases. [provided by RefSeq, Mar 2017]

SPTLC3 links:

CENATACP1 (HGNC:56949):

CENATACP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.1749 (below the threshold of 3.09). Trascript score misZ: 1.0407 (below the threshold of 3.09).

BP4

Computational evidence support a benign effect (MetaRNN=0.2737503).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018327.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTLC3	NM_018327.4	MANE Select	c.606G>A	p.Met202Ile	missense splice_region	Exon 4 of 12	NP_060797.2	Q9NUV7-1
	SPTLC3	NM_001349945.2		c.606G>A	p.Met202Ile	missense splice_region	Exon 5 of 13	NP_001336874.1	Q9NUV7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPTLC3	ENST00000399002.7	TSL:1 MANE Select	c.606G>A	p.Met202Ile	missense splice_region	Exon 4 of 12	ENSP00000381968.2	Q9NUV7-1
SPTLC3	ENST00000966145.1		c.606G>A	p.Met202Ile	missense splice_region	Exon 4 of 12	ENSP00000636204.1
SPTLC3	ENST00000450297.1	TSL:3	c.525G>A	p.Met175Ile	missense splice_region	Exon 4 of 5	ENSP00000409125.1	B1AKS3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457170

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724412

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33312

American (AMR)

AF:

0.00

AC:

AN:

44020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25940

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00

AC:

AN:

85226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109784

Other (OTH)

AF:

0.00

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.13

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.67

M_CAP

Benign

0.058

MetaRNN

Benign

0.27

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

-0.47

PhyloP100

4.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.54

REVEL

Uncertain

0.33

Sift

Benign

0.55

Sift4G

Benign

0.57

Polyphen

0.016

Vest4

0.28

MutPred

0.45

Loss of ubiquitination at K207 (P = 0.064)

MVP

0.65

MPC

0.24

ClinPred

0.70

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.67

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00030

dbscSNV1_RF

Benign

0.056

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

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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