chr17-6686223-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_177550.5(SLC13A5):​c.1691C>T​(p.Thr564Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC13A5
NM_177550.5 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.25
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)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32378423).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC13A5NM_177550.5 linkuse as main transcriptc.1691C>T p.Thr564Ile missense_variant 12/12 ENST00000433363.7
SLC13A5NM_001284509.2 linkuse as main transcriptc.1640C>T p.Thr547Ile missense_variant 12/12
SLC13A5NM_001284510.2 linkuse as main transcriptc.1562C>T p.Thr521Ile missense_variant 11/11
SLC13A5NM_001143838.3 linkuse as main transcriptc.1553C>T p.Thr518Ile missense_variant 11/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC13A5ENST00000433363.7 linkuse as main transcriptc.1691C>T p.Thr564Ile missense_variant 12/121 NM_177550.5 P1Q86YT5-1
ENST00000634558.1 linkuse as main transcriptn.511-3653G>A intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152176
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251368
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135868
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461878
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152176
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

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 testingInvitaeMay 07, 2022This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 564 of the SLC13A5 protein (p.Thr564Ile). This variant is present in population databases (rs771551520, gnomAD 0.0009%). 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: 1014097). 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: "Deleterious"; 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
0.58
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
D;.;.;.
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.72
T;T;T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.32
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.7
.;.;D;.
REVEL
Benign
0.27
Sift
Benign
0.084
.;.;T;.
Sift4G
Benign
0.091
T;T;T;T
Polyphen
1.0
D;.;.;.
Vest4
0.44
MVP
0.55
MPC
0.60
ClinPred
0.97
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.34
gMVP
0.80

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: rs771551520; hg19: chr17-6589542; API