Genetic Variant NM_018327.4:c.418T>G (chr20-13072370-T-G) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2BP4_StrongBA1

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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.78 ( 47334 hom., cov: 32)

Exomes 𝑓: 0.72 ( 382111 hom. )

Consequence

SPTLC3
NM_018327.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.776

Publications

39 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 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).

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 link	c.418T>G	p.Leu140Val	missense_variant	Exon 3 of 12	ENST00000399002.7	NP_060797.2	Q9NUV7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPTLC3	ENST00000399002.7 link	c.418T>G	p.Leu140Val	missense_variant	Exon 3 of 12	1	NM_018327.4	ENSP00000381968.2	Q9NUV7-1
SPTLC3	ENST00000450297.1 link	c.337T>G	p.Leu113Val	missense_variant	Exon 3 of 5	3		ENSP00000409125.1	B1AKS3
SPTLC3	ENST00000434210.5 link	c.418T>G	p.???140???	splice_region_variant, synonymous_variant	Exon 4 of 4	3		ENSP00000389749.1	B1AKS2

Frequencies

GnomAD3 genomes

AF:

0.781

AC:

118776

AN:

152022

Hom.:

47274

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.717

AC XY:

520590

AN XY:

725626

show subpopulations

African (AFR)

AF:

0.948

AC:

31668

AN:

33416

American (AMR)

AF:

0.707

AC:

31458

AN:

44468

Ashkenazi Jewish (ASJ)

AF:

0.776

AC:

20216

AN:

26058

East Asian (EAS)

AF:

0.531

AC:

21076

AN:

39656

South Asian (SAS)

AF:

0.600

AC:

51520

AN:

85914

European-Finnish (FIN)

AF:

0.717

AC:

38266

AN:

53402

Middle Eastern (MID)

AF:

0.793

AC:

4570

AN:

5760

European-Non Finnish (NFE)

AF:

0.728

AC:

807877

AN:

1109374

Other (OTH)

AF:

0.742

AC:

44748

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

13762

27523

41285

55046

68808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19926

39852

59778

79704

99630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.781

AC:

118892

AN:

152140

Hom.:

47334

Cov.:

AF XY:

0.776

AC XY:

57735

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.939

AC:

39000

AN:

41550

American (AMR)

AF:

0.756

AC:

11539

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.779

AC:

2701

AN:

3468

East Asian (EAS)

AF:

0.590

AC:

3045

AN:

5164

South Asian (SAS)

AF:

0.587

AC:

2827

AN:

4814

European-Finnish (FIN)

AF:

0.715

AC:

7559

AN:

10578

Middle Eastern (MID)

AF:

0.793

AC:

233

AN:

294

European-Non Finnish (NFE)

AF:

0.733

AC:

49808

AN:

67982

Other (OTH)

AF:

0.784

AC:

1655

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1301

2603

3904

5206

6507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

852

1704

2556

3408

4260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.34

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.038

T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.49

T;T

MetaRNN

Benign

8.0e-7

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.26

N;.

PhyloP100

-0.78

PrimateAI

Benign

0.28

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

GERP RS

-6.3

Varity_R

0.035

gMVP

0.64

Mutation Taster

=99/1

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over