20-13072400-T-C

Variant names:

• chr20-13072400-T-C
• rs755919784
• NM_018327.4:c.448T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_018327.4(SPTLC3):​c.448T>C​(p.Trp150Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000326 in 1,593,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: SPTLC3 NM_018327.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.05

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: Likely_pathogenic. The variant received 6 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).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79
• PP5: Variant 20-13072400-T-C is Pathogenic according to our data. Variant chr20-13072400-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 243088.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTLC3	NM_018327.4	c.448T>C	p.Trp150Arg	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.448T>C	p.Trp150Arg	missense_variant	Exon 3 of 12	1	NM_018327.4	ENSP00000381968.2
SPTLC3	ENST00000450297.1	c.367T>C	p.Trp123Arg	missense_variant	Exon 3 of 5	3		ENSP00000409125.1
SPTLC3	ENST00000434210.5	c.*29T>C		downstream_gene_variant		3		ENSP00000389749.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000263 AC: 6 AN: 227768 AF XY: 0.0000242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000356

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000467

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000347 AC: 50 AN: 1441150 Hom.: 0 Cov.: 32 AF XY: 0.0000391 AC XY: 28 AN XY: 716618

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 31956

Gnomad4 AMR exome AF: 0.0000252 AC: 1 AN: 39652

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25142

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39352

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 82356

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53128

Gnomad4 NFE exome AF: 0.0000435 AC: 48 AN: 1104560

Gnomad4 Remaining exome AF: 0.0000168 AC: 1 AN: 59354

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241336 AN: 0.0000241336

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000146998 AN: 0.0000146998

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peripheral neuropathy;C0151313:Sensory neuropathy Pathogenic:1

Aug 18, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Likely pathogenic based on conservation and prediction scores (Phylop, LRT, Polyphen, MutationTaster). Variant identified in male with peripheral neuropathy with marked sensory involvement. Supported by literature indicating interaction with known neuropathy genes, and by zebrafish functional assay (PMID: 26257172). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-13	D;D
REVEL	Uncertain	0.50
Sift	Benign	0.42	T;D
Sift4G	Benign	0.75	T;D
Polyphen		1.0	D;.
Vest4		0.48
MutPred		0.53		Gain of disorder (P = 0.0138);.;
MVP		0.72
MPC		1.1
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.72
gMVP		0.85
Mutation Taster		=16/84	disease causing (ClinVar)

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: rs755919784; hg19: chr20-13053048;