rs119482084

Variant names:

• chr9-92038342-C-G
• rs119482084
• NM_006415.4:c.1160G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-92038342-C-G
• chr9-92038342-C-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_006415.4(SPTLC1):​c.1160G>C​(p.Gly387Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000557 in 1,613,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G387E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: SPTLC1 NM_006415.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:8 O:1
• Conservation: PhyloP100: 6.89
• Publications: 21 publications found

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

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833
• BP6: Variant 9-92038342-C-G is Benign according to our data. Variant chr9-92038342-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 4802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000388 (59/152234) while in subpopulation AMR AF = 0.000784 (12/15302). AF 95% confidence interval is 0.000452. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 59 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTLC1	NM_006415.4	MANE Select	c.1160G>C	p.Gly387Ala	missense	Exon 13 of 15	NP_006406.1	O15269-1
	SPTLC1	NM_001281303.2		c.1160G>C	p.Gly387Ala	missense	Exon 13 of 15	NP_001268232.1
	SPTLC1	NM_001368272.1		c.794G>C	p.Gly265Ala	missense	Exon 14 of 16	NP_001355201.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTLC1	ENST00000262554.7	TSL:1 MANE Select	c.1160G>C	p.Gly387Ala	missense	Exon 13 of 15	ENSP00000262554.2	O15269-1
	SPTLC1	ENST00000953500.1		c.1370G>C	p.Gly457Ala	missense	Exon 14 of 16	ENSP00000623559.1
	SPTLC1	ENST00000884978.1		c.1160G>C	p.Gly387Ala	missense	Exon 13 of 16	ENSP00000555037.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000429 AC: 108 AN: 251488 AF XY: 0.000331

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000633

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000574 AC: 839 AN: 1461390 Hom.: 0 Cov.: 30 AF XY: 0.000575 AC XY: 418 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86250

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000672 AC: 747 AN: 1111544

Other (OTH) AF: 0.000596 AC: 36 AN: 60376

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74418

African (AFR) AF: 0.0000964 AC: 4 AN: 41506

American (AMR) AF: 0.000784 AC: 12 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000681 Hom.: 0

Bravo AF: 0.000397

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000379 AC: 46

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	1	Charcot-Marie-Tooth disease (2)
-	1	1	Hereditary sensory and autonomic neuropathy type 1 (2)
-	-	2	Neuropathy, hereditary sensory and autonomic, type 1A (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.9
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.032	D
Polyphen		0.41	B
Vest4		0.92
MVP		0.89
MPC		1.1
ClinPred		0.25	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.80
Mutation Taster		=2/98	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: rs119482084; hg19: chr9-94800624; COSMIC: COSV99364672;