chr20-13049098-T-G

Variant names:

• chr20-13049098-T-G
• rs757704377
• NM_018327.4:c.271T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_018327.4(SPTLC3):​c.271T>G​(p.Cys91Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTLC3 NM_018327.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88
• Publications: 0 publications found

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: Uncertain_significance. The variant received 4 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, 0.796

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.271T>G	p.Cys91Gly	missense	Exon 2 of 12	NP_060797.2	Q9NUV7-1
	SPTLC3	NM_001349945.2		c.271T>G	p.Cys91Gly	missense	Exon 3 of 13	NP_001336874.1	Q9NUV7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTLC3	ENST00000399002.7	TSL:1 MANE Select	c.271T>G	p.Cys91Gly	missense	Exon 2 of 12	ENSP00000381968.2	Q9NUV7-1
	SPTLC3	ENST00000476791.1	TSL:1	n.560T>G		non_coding_transcript_exon	Exon 2 of 2
	SPTLC3	ENST00000966145.1		c.271T>G	p.Cys91Gly	missense	Exon 2 of 12	ENSP00000636204.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.025	D
Polyphen		0.24	B
Vest4		0.61
MutPred		0.63		Gain of disorder (P = 0.003)
MVP		0.67
MPC		0.77
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.57
gMVP		0.64
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs757704377; hg19: chr20-13029746;