Genetic Variant NM_006415.4:c.452G>T (chr9-92068074-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006415.4(SPTLC1):c.452G>T(p.Arg151Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0223 in 1,613,754 control chromosomes in the GnomAD database, including 468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R151S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 35 hom., cov: 32)

Exomes 𝑓: 0.023 ( 433 hom. )

Consequence

SPTLC1
NM_006415.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.97

Publications

17 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 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis 27, juvenile
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
neuropathy, hereditary sensory and autonomic, type 1A
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
hereditary sensory and autonomic neuropathy type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPTLC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0135652125).

BP6

Variant 9-92068074-C-A is Benign according to our data. Variant chr9-92068074-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 367550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0174 (2644/152248) while in subpopulation NFE AF = 0.0263 (1788/68020). AF 95% confidence interval is 0.0253. There are 35 homozygotes in GnomAd4. There are 1232 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2644 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006415.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPTLC1	NM_006415.4	MANE Select	c.452G>T	p.Arg151Leu	missense	Exon 6 of 15	NP_006406.1	O15269-1
SPTLC1	NM_001281303.2		c.452G>T	p.Arg151Leu	missense	Exon 6 of 15	NP_001268232.1
SPTLC1	NM_001368272.1		c.86G>T	p.Arg29Leu	missense	Exon 7 of 16	NP_001355201.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPTLC1	ENST00000262554.7	TSL:1 MANE Select	c.452G>T	p.Arg151Leu	missense	Exon 6 of 15	ENSP00000262554.2	O15269-1
SPTLC1	ENST00000953500.1		c.662G>T	p.Arg221Leu	missense	Exon 7 of 16	ENSP00000623559.1
SPTLC1	ENST00000884978.1		c.452G>T	p.Arg151Leu	missense	Exon 6 of 16	ENSP00000555037.1

Frequencies

GnomAD3 genomes

AF:

0.0174

AC:

2644

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0135

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0193

Gnomad FIN

AF:

0.0178

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0263

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.0202

AC:

5073

AN:

250894

AF XY:

0.0213

show subpopulations

Gnomad AFR exome

AF:

0.00339

Gnomad AMR exome

AF:

0.0112

Gnomad ASJ exome

AF:

0.0309

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0185

Gnomad NFE exome

AF:

0.0286

Gnomad OTH exome

AF:

0.0289

GnomAD4 exome

AF:

0.0228

AC:

33384

AN:

1461506

Hom.:

433

Cov.:

AF XY:

0.0230

AC XY:

16693

AN XY:

727046

show subpopulations

African (AFR)

AF:

0.00278

AC:

AN:

33470

American (AMR)

AF:

0.0118

AC:

526

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0315

AC:

824

AN:

26126

East Asian (EAS)

AF:

0.000151

AC:

AN:

39648

South Asian (SAS)

AF:

0.0178

AC:

1536

AN:

86228

European-Finnish (FIN)

AF:

0.0200

AC:

1067

AN:

53372

Middle Eastern (MID)

AF:

0.0293

AC:

169

AN:

5768

European-Non Finnish (NFE)

AF:

0.0250

AC:

27811

AN:

1111812

Other (OTH)

AF:

0.0224

AC:

1352

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

1691

3382

5074

6765

8456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1010

2020

3030

4040

5050

<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:

0.0174

AC:

2644

AN:

152248

Hom.:

Cov.:

AF XY:

0.0166

AC XY:

1232

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00448

AC:

186

AN:

41536

American (AMR)

AF:

0.0135

AC:

207

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0337

AC:

117

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0193

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0178

AC:

189

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0263

AC:

1788

AN:

68020

Other (OTH)

AF:

0.0213

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

135

270

404

539

674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0232

Hom.:

179

Bravo

AF:

0.0162

TwinsUK

AF:

0.0240

AC:

ALSPAC

AF:

0.0239

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0291

AC:

250

ExAC

AF:

0.0216

AC:

2621

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0274

EpiControl

AF:

0.0255

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Charcot-Marie-Tooth disease (1)

Hereditary sensory and autonomic neuropathy type 1 (1)

Neuropathy, hereditary sensory and autonomic, type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Benign

-0.0056

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.75

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.011

MutationAssessor

Benign

1.2

PhyloP100

4.0

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.48

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0040

Polyphen

0.013

Vest4

0.32

MPC

0.75

ClinPred

0.080

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.91

Mutation Taster

=75/25

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over