NM_006415.4:c.208G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_006415.4(SPTLC1):c.208G>T(p.Val70Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,605,282 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

SPTLC1
NM_006415.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.60

Publications

0 publications found

Variant links:

Genes affected

SPTLC1 (HGNC:11277): (serine palmitoyltransferase long chain base subunit 1) This gene encodes a member of the class-II pyridoxal-phosphate-dependent aminotransferase family. The encoded protein is the long chain base subunit 1 of serine palmitoyltransferase. Serine palmitoyltransferase converts L-serine and palmitoyl-CoA to 3-oxosphinganine with pyridoxal 5'-phosphate and is the key enzyme in sphingolipid biosynthesis. Mutations in this gene were identified in patients with hereditary sensory neuropathy type 1. Alternatively spliced variants encoding different isoforms have been identified. Pseudogenes of this gene have been defined on chromosomes 1, 6, 10, and 13. [provided by RefSeq, Jul 2013]

SPTLC1 links:

MTATP6P29 (HGNC:52187): (MT-ATP6 pseudogene 29)

MTATP6P29 links:

MTCO3P29 (HGNC:52132): (MT-CO3 pseudogene 29)

MTCO3P29 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 9-92108792-C-A is Benign according to our data. Variant chr9-92108792-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234709.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000526 (8/152104) while in subpopulation NFE AF = 0.000118 (8/68010). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTLC1	NM_006415.4 link	c.208G>T	p.Val70Phe	missense_variant	Exon 3 of 15	ENST00000262554.7	NP_006406.1	O15269-1A0A024R277Q6NUL7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTLC1	ENST00000262554.7 link	c.208G>T	p.Val70Phe	missense_variant	Exon 3 of 15	1	NM_006415.4	ENSP00000262554.2		O15269-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000813

AC:

AN:

245978

AF XY:

0.0000972

show subpopulations

Gnomad AFR exome

AF:

0.0000661

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000152

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000150

AC:

218

AN:

1453178

Hom.:

Cov.:

AF XY:

0.000126

AC XY:

AN XY:

722360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33078

American (AMR)

AF:

0.00

AC:

AN:

44188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.00

AC:

AN:

39588

South Asian (SAS)

AF:

0.00

AC:

AN:

85534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4170

European-Non Finnish (NFE)

AF:

0.000191

AC:

211

AN:

1107314

Other (OTH)

AF:

0.000117

AC:

AN:

59952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.0000526

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000142

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000907

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 27, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20097765, 16364956) -

Hereditary sensory and autonomic neuropathy type 1

Uncertain:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 70 of the SPTLC1 protein (p.Val70Phe). This variant is present in population databases (rs764460003, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SPTLC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 234709). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SPTLC1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Mar 13, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

3.3

M;M

PhyloP100

5.6

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.5

D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.99

D;.

Vest4

0.68

MVP

0.88

MPC

1.1

ClinPred

0.91

GERP RS

4.8

Varity_R

0.77

gMVP

0.96

Mutation Taster

=18/82

disease causing

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over