rs243887

Variant names:

• chr20-13072370-T-G
• rs243887
• NM_018327.4:c.418T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BA1

The NM_018327.4(SPTLC3):​c.418T>G​(p.Leu140Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 1,610,458 control chromosomes in the GnomAD database, including 429,445 homozygotes. 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 Lovd as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.78 (47334 hom., cov: 32)
  • Exomes 𝑓: 0.72 (382111 hom.)
• Consequence: SPTLC3 NM_018327.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.776

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• 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=8.0261486E-7).
• BP6: Variant 20-13072370-T-G is Benign according to our data. Variant chr20-13072370-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTLC3	NM_018327.4	c.418T>G	p.Leu140Val	missense_variant	Exon 3 of 12	ENST00000399002.7	NP_060797.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTLC3	ENST00000399002.7	c.418T>G	p.Leu140Val	missense_variant	Exon 3 of 12	1	NM_018327.4	ENSP00000381968.2
SPTLC3	ENST00000450297.1	c.337T>G	p.Leu113Val	missense_variant	Exon 3 of 5	3		ENSP00000409125.1
SPTLC3	ENST00000434210.5	c.418T>G	p.???140???	splice_region_variant, synonymous_variant	Exon 4 of 4	3		ENSP00000389749.1

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118776 AN: 152022 Hom.: 47274 Cov.: 32

Gnomad AFR AF: 0.938

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.784

GnomAD2 exomes AF: 0.713 AC: 176786 AN: 247826 AF XY: 0.708

Gnomad AFR exome AF: 0.941

Gnomad AMR exome AF: 0.702

Gnomad ASJ exome AF: 0.773

Gnomad EAS exome AF: 0.586

Gnomad FIN exome AF: 0.717

Gnomad NFE exome AF: 0.730

Gnomad OTH exome AF: 0.735

GnomAD4 exome AF: 0.721 AC: 1051399 AN: 1458318 Hom.: 382111 Cov.: 44 AF XY: 0.717 AC XY: 520590 AN XY: 725626

Gnomad4 AFR exome AF: 0.948 AC: 31668 AN: 33416

Gnomad4 AMR exome AF: 0.707 AC: 31458 AN: 44468

Gnomad4 ASJ exome AF: 0.776 AC: 20216 AN: 26058

Gnomad4 EAS exome AF: 0.531 AC: 21076 AN: 39656

Gnomad4 SAS exome AF: 0.600 AC: 51520 AN: 85914

Gnomad4 FIN exome AF: 0.717 AC: 38266 AN: 53402

Gnomad4 NFE exome AF: 0.728 AC: 807877 AN: 1109374

Gnomad4 Remaining exome AF: 0.742 AC: 44748 AN: 60270

GnomAD4 genome AF: 0.781 AC: 118892 AN: 152140 Hom.: 47334 Cov.: 32 AF XY: 0.776 AC XY: 57735 AN XY: 74380

Gnomad4 AFR AF: 0.939 AC: 0.938628 AN: 0.938628

Gnomad4 AMR AF: 0.756 AC: 0.755665 AN: 0.755665

Gnomad4 ASJ AF: 0.779 AC: 0.778835 AN: 0.778835

Gnomad4 EAS AF: 0.590 AC: 0.589659 AN: 0.589659

Gnomad4 SAS AF: 0.587 AC: 0.587246 AN: 0.587246

Gnomad4 FIN AF: 0.715 AC: 0.714596 AN: 0.714596

Gnomad4 NFE AF: 0.733 AC: 0.732665 AN: 0.732665

Gnomad4 OTH AF: 0.784 AC: 0.783617 AN: 0.783617

Alfa AF: 0.748 Hom.: 150639

Bravo AF: 0.793

TwinsUK AF: 0.737 AC: 2731

ALSPAC AF: 0.734 AC: 2827

ESP6500AA AF: 0.932 AC: 3414

ESP6500EA AF: 0.734 AC: 6000

ExAC AF: 0.714 AC: 86195

Asia WGS AF: 0.633 AC: 2203 AN: 3476

EpiCase AF: 0.752

EpiControl AF: 0.744

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.34
DANN	Benign	0.68
DEOGEN2	Benign	0.038	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	8.0e-7	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.26	N;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.53	N;N
REVEL	Benign	0.037
Sift	Benign	0.55	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0040	B;.
Vest4		0.019
MPC		0.21
ClinPred		0.0021	T
GERP RS		-6.3
Varity_R		0.035
gMVP		0.64
Mutation Taster		=99/1	polymorphism (auto)

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: rs243887; hg19: chr20-13053018; COSMIC: COSV65464058; COSMIC: COSV65464058;