chr14-34462156-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_138288.4(SPTSSA):ā€‹c.52T>Gā€‹(p.Tyr18Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000261 in 1,531,216 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 Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y18N) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 29)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

SPTSSA
NM_138288.4 missense

Scores

8
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.75
Variant links:
Genes affected
SPTSSA (HGNC:20361): (serine palmitoyltransferase small subunit A) Serine palmitoyltransferase (SPT; EC 2.3.1.50) catalyzes the first committed and rate-limiting step in sphingolipid biosynthesis. SSSPTA is a small SPT subunit that stimulates SPT activity and confers acyl-CoA preference to the SPT catalytic heterodimer of SPTLC1 (MIM 605712) and either SPTLC2 (MIM 605713) or SPTLC3 (MIM 611120) (Han et al., 2009 [PubMed 19416851]).[supplied by OMIM, Nov 2010]
EGLN3 (HGNC:14661): (egl-9 family hypoxia inducible factor 3) Enables peptidyl-proline 4-dioxygenase activity. Involved in several processes, including activation of cysteine-type endopeptidase activity involved in apoptotic process; peptidyl-proline hydroxylation to 4-hydroxy-L-proline; and response to hypoxia. Located in cytosol and nucleus. Implicated in renal cell carcinoma. Biomarker of clear cell renal cell carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SPTSSANM_138288.4 linkuse as main transcriptc.52T>G p.Tyr18Asp missense_variant 1/2 ENST00000298130.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SPTSSAENST00000298130.5 linkuse as main transcriptc.52T>G p.Tyr18Asp missense_variant 1/21 NM_138288.4 P1
EGLN3ENST00000551935.5 linkuse as main transcriptn.59+560T>G intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.0000133
AC:
2
AN:
150142
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.0000487
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000145
AC:
2
AN:
1381074
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
687348
show subpopulations
Gnomad4 AFR exome
AF:
0.0000356
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000180
GnomAD4 genome
AF:
0.0000133
AC:
2
AN:
150142
Hom.:
0
Cov.:
29
AF XY:
0.0000136
AC XY:
1
AN XY:
73268
show subpopulations
Gnomad4 AFR
AF:
0.0000487
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 20, 2021The c.52T>G (p.Y18D) alteration is located in exon 1 (coding exon 1) of the SPTSSA gene. This alteration results from a T to G substitution at nucleotide position 52, causing the tyrosine (Y) at amino acid position 18 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.45
T
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.79
T
M_CAP
Pathogenic
0.85
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Benign
-0.53
T
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-7.0
D
REVEL
Pathogenic
0.71
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.013
D
Polyphen
0.71
P
Vest4
0.86
MutPred
0.53
Gain of catalytic residue at M13 (P = 0);
MVP
0.29
MPC
1.1
ClinPred
0.99
D
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.93
gMVP
0.99

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1043206248; hg19: chr14-34931362; API