11-26681123-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_178498.4(SLC5A12):​c.1407G>C​(p.Leu469Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,611,248 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 (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

SLC5A12
NM_178498.4 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01
Variant links:
Genes affected
SLC5A12 (HGNC:28750): (solute carrier family 5 member 12) Normal blood lactate is maintained at about 1.5 mM, and little filtered lactate is excreted in urine. Reabsorption of lactate is mediated by the low-affinity Na(+)-coupled lactate transporter SLC5A12 in the initial part of the proximal tubule and by the high-affinity Na(+)-coupled lactate transporter SLC5A8 (MIM 608044) in the distal proximal tubule (Gopal et al., 2007 [PubMed 17692818]).[supplied by OMIM, Dec 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC5A12NM_178498.4 linkc.1407G>C p.Leu469Phe missense_variant Exon 12 of 15 ENST00000396005.8 NP_848593.2 Q1EHB4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC5A12ENST00000396005.8 linkc.1407G>C p.Leu469Phe missense_variant Exon 12 of 15 1 NM_178498.4 ENSP00000379326.3 Q1EHB4-1
SLC5A12ENST00000527405.5 linkn.*13G>C non_coding_transcript_exon_variant Exon 12 of 15 2 ENSP00000436011.1 G3V1E3
SLC5A12ENST00000527405.5 linkn.*13G>C 3_prime_UTR_variant Exon 12 of 15 2 ENSP00000436011.1 G3V1E3

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152178
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:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000608
AC:
15
AN:
246844
Hom.:
0
AF XY:
0.0000597
AC XY:
8
AN XY:
133946
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:
0.000134
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000274
AC:
400
AN:
1459070
Hom.:
0
Cov.:
34
AF XY:
0.000263
AC XY:
191
AN XY:
725798
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
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:
0.000357
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74326
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:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000224
Hom.:
0
Bravo
AF:
0.0000680
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000242
AC:
2
ExAC
AF:
0.0000497
AC:
6

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1407G>C (p.L469F) alteration is located in exon 12 (coding exon 12) of the SLC5A12 gene. This alteration results from a G to C substitution at nucleotide position 1407, causing the leucine (L) at amino acid position 469 to be replaced by a phenylalanine (F). 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
Uncertain
0.42
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.19
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Benign
0.75
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.051
D
MetaRNN
Pathogenic
0.79
D
MetaSVM
Benign
-0.38
T
MutationAssessor
Pathogenic
3.8
H
PrimateAI
Benign
0.43
T
PROVEAN
Uncertain
-3.5
D
REVEL
Uncertain
0.35
Sift
Uncertain
0.0060
D
Sift4G
Uncertain
0.013
D
Polyphen
1.0
D
Vest4
0.65
MutPred
0.43
Loss of loop (P = 0.0203);
MVP
0.79
MPC
0.79
ClinPred
0.94
D
GERP RS
3.6
Varity_R
0.27
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.18
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: rs374581708; hg19: chr11-26702670; API