chr17-6686286-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_177550.5(SLC13A5):​c.1628C>A​(p.Ala543Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,066 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A543S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

SLC13A5
NM_177550.5 missense

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60
Variant links:
Genes affected
SLC13A5 (HGNC:23089): (solute carrier family 13 member 5) This gene encodes a protein belonging to the solute carrier family 13 group of proteins. This family member is a sodium-dependent citrate cotransporter that may regulate metabolic processes. Mutations in this gene cause early infantile epileptic encephalopathy 25. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]
C17orf100 (HGNC:34494): (chromosome 17 open reading frame 100)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC13A5NM_177550.5 linkuse as main transcriptc.1628C>A p.Ala543Asp missense_variant 12/12 ENST00000433363.7
SLC13A5NM_001284509.2 linkuse as main transcriptc.1577C>A p.Ala526Asp missense_variant 12/12
SLC13A5NM_001284510.2 linkuse as main transcriptc.1499C>A p.Ala500Asp missense_variant 11/11
SLC13A5NM_001143838.3 linkuse as main transcriptc.1490C>A p.Ala497Asp missense_variant 11/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC13A5ENST00000433363.7 linkuse as main transcriptc.1628C>A p.Ala543Asp missense_variant 12/121 NM_177550.5 P1Q86YT5-1
ENST00000634558.1 linkuse as main transcriptn.511-3590G>T intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.000576
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
GnomAD3 exomes
AF:
0.0000240
AC:
6
AN:
250302
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135388
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461874
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.000268
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:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.000576
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
Alfa
AF:
0.0000900
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

Developmental and epileptic encephalopathy, 25 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 01, 2022This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 543 of the SLC13A5 protein (p.Ala543Asp). This variant is present in population databases (rs202208840, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SLC13A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 541967). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Uncertain
0.060
T
BayesDel_noAF
Uncertain
-0.070
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;.;.;.
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Benign
0.056
D
MetaRNN
Pathogenic
0.96
D;D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Pathogenic
3.5
M;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.48
T
PROVEAN
Pathogenic
-4.4
.;.;D;.
REVEL
Uncertain
0.46
Sift
Uncertain
0.0020
.;.;D;.
Sift4G
Uncertain
0.020
D;D;D;D
Polyphen
0.27
B;.;.;.
Vest4
0.80
MutPred
0.90
Loss of stability (P = 0.3066);.;.;.;
MVP
0.51
MPC
0.92
ClinPred
0.96
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.95
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs202208840; hg19: chr17-6589605; API