rs7944

Variant names:

• chr9-92032020-T-C
• rs7944
• NM_006415.4:c.*445A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006415.4(SPTLC1):​c.*445A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 402,286 control chromosomes in the GnomAD database, including 715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (264 hom., cov: 32)
  • Exomes 𝑓: 0.055 (451 hom.)
• Consequence: SPTLC1 NM_006415.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.33
• Publications: 11 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-92032020-T-C is Benign according to our data. Variant chr9-92032020-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 367538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0598 is higher than 0.05.

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.*445A>G		3_prime_UTR	Exon 15 of 15	NP_006406.1	O15269-1
	SPTLC1	NM_001281303.2		c.*293A>G		3_prime_UTR	Exon 15 of 15	NP_001268232.1
	SPTLC1	NM_001368272.1		c.*445A>G		3_prime_UTR	Exon 16 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.*445A>G		3_prime_UTR	Exon 15 of 15	ENSP00000262554.2	O15269-1
	SPTLC1	ENST00000953500.1		c.*445A>G		3_prime_UTR	Exon 16 of 16	ENSP00000623559.1
	SPTLC1	ENST00000686600.1		c.*579A>G		3_prime_UTR	Exon 16 of 16	ENSP00000509268.1	A0A8I5KUM4

Frequencies

GnomAD3 genomes AF: 0.0519 AC: 7892 AN: 152156 Hom.: 264 Cov.: 32

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0470

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0862

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0613

Gnomad OTH AF: 0.0612

GnomAD4 exome AF: 0.0545 AC: 13630 AN: 250012 Hom.: 451 Cov.: 2 AF XY: 0.0542 AC XY: 6906 AN XY: 127502

African (AFR) AF: 0.0309 AC: 235 AN: 7598

American (AMR) AF: 0.0443 AC: 405 AN: 9146

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 1092 AN: 8944

East Asian (EAS) AF: 0.0000950 AC: 2 AN: 21058

South Asian (SAS) AF: 0.0142 AC: 169 AN: 11934

European-Finnish (FIN) AF: 0.0836 AC: 1265 AN: 15140

Middle Eastern (MID) AF: 0.0762 AC: 93 AN: 1220

European-Non Finnish (NFE) AF: 0.0593 AC: 9418 AN: 158856

Other (OTH) AF: 0.0590 AC: 951 AN: 16116

GnomAD4 genome AF: 0.0519 AC: 7903 AN: 152274 Hom.: 264 Cov.: 32 AF XY: 0.0517 AC XY: 3852 AN XY: 74466

African (AFR) AF: 0.0326 AC: 1355 AN: 41566

American (AMR) AF: 0.0469 AC: 717 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 454 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4828

European-Finnish (FIN) AF: 0.0862 AC: 914 AN: 10598

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0613 AC: 4170 AN: 68016

Other (OTH) AF: 0.0605 AC: 128 AN: 2114

Alfa AF: 0.0601 Hom.: 348

Bravo AF: 0.0487

Asia WGS AF: 0.0120 AC: 43 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Neuropathy, hereditary sensory and autonomic, type 1A (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.20
DANN	Benign	0.43
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs7944; hg19: chr9-94794302;