Genetic Variant SPTLC1:c.*178T>A (chr9-92032287-A-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_006415.4(SPTLC1):c.*178T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000714 in 1,529,302 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 2 hom. )

Consequence

SPTLC1
NM_006415.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.475

Publications

1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
neuropathy, hereditary sensory and autonomic, type 1A
Inheritance: AD Classification: STRONG Submitted by: 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 9-92032287-A-T is Benign according to our data. Variant chr9-92032287-A-T is described in ClinVar as Benign. ClinVar VariationId is 367541.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000887 (135/152132) while in subpopulation AMR AF = 0.00321 (49/15274). AF 95% confidence interval is 0.00249. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 135 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	Effect	Exon Rank	Protein	UniProt
SPTLC1	NM_006415.4	MANE Select	c.*178T>A	3_prime_UTR	Exon 15 of 15	NP_006406.1	O15269-1
SPTLC1	NM_001281303.2		c.*26T>A	3_prime_UTR	Exon 15 of 15	NP_001268232.1
SPTLC1	NM_001368272.1		c.*178T>A	3_prime_UTR	Exon 16 of 16	NP_001355201.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SPTLC1	ENST00000262554.7	TSL:1 MANE Select	c.*178T>A	3_prime_UTR	Exon 15 of 15	ENSP00000262554.2	O15269-1
SPTLC1	ENST00000953500.1		c.*178T>A	3_prime_UTR	Exon 16 of 16	ENSP00000623559.1
SPTLC1	ENST00000884978.1		c.*178T>A	3_prime_UTR	Exon 16 of 16	ENSP00000555037.1

Frequencies

GnomAD3 genomes

AF:

0.000881

AC:

134

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000839

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000726

AC:

AN:

132208

AF XY:

0.000618

show subpopulations

Gnomad AFR exome

AF:

0.000599

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.000127

Gnomad EAS exome

AF:

0.0000924

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000536

Gnomad OTH exome

AF:

0.00325

GnomAD4 exome

AF:

0.000695

AC:

957

AN:

1377170

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

474

AN XY:

679152

show subpopulations

African (AFR)

AF:

0.000609

AC:

AN:

31178

American (AMR)

AF:

0.00257

AC:

AN:

34668

Ashkenazi Jewish (ASJ)

AF:

0.000120

AC:

AN:

24906

East Asian (EAS)

AF:

0.0000841

AC:

AN:

35666

South Asian (SAS)

AF:

0.000281

AC:

AN:

78174

European-Finnish (FIN)

AF:

0.0000292

AC:

AN:

34252

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.000726

AC:

781

AN:

1075092

Other (OTH)

AF:

0.000660

AC:

AN:

57582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

104

157

209

261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000887

AC:

135

AN:

152132

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.000530

AC:

AN:

41532

American (AMR)

AF:

0.00321

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000839

AC:

AN:

67964

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00119

Hom.:

Bravo

AF:

0.000918

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.0

(source)

DANN

Benign

0.42

PhyloP100

0.47

Mutation Taster

=100/0

polymorphism

(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