20-49880945-G-A

Variant summary

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

The NM_015266.3(SLC9A8):​c.1180G>A​(p.Ala394Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,220 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

SLC9A8
NM_015266.3 missense

Scores

8
5
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.82
Variant links:
Genes affected
SLC9A8 (HGNC:20728): (solute carrier family 9 member A8) Sodium-hydrogen exchangers (NHEs), such as SLC9A8, are integral transmembrane proteins that exchange extracellular Na+ for intracellular H+. NHEs have multiple functions, including intracellular pH homeostasis, cell volume regulation, and electroneutral NaCl absorption in epithelia (Xu et al., 2008 [PubMed 18209477]).[supplied by OMIM, Apr 2009]

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, 0.866

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC9A8NM_015266.3 linkc.1180G>A p.Ala394Thr missense_variant Exon 13 of 16 ENST00000361573.3 NP_056081.1 Q9Y2E8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC9A8ENST00000361573.3 linkc.1180G>A p.Ala394Thr missense_variant Exon 13 of 16 1 NM_015266.3 ENSP00000354966.2 Q9Y2E8-1
SLC9A8ENST00000417961.5 linkc.1228G>A p.Ala410Thr missense_variant Exon 13 of 16 2 ENSP00000416418.1 Q9Y2E8-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251476
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.0000527
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461006
Hom.:
0
Cov.:
30
AF XY:
0.0000151
AC XY:
11
AN XY:
726890
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000810
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152214
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000494
AC:
6

ClinVar

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

Submissions by phenotype

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

The c.1180G>A (p.A394T) alteration is located in exon 13 (coding exon 13) of the SLC9A8 gene. This alteration results from a G to A substitution at nucleotide position 1180, causing the alanine (A) at amino acid position 394 to be replaced by a threonine (T). 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
0.63
BayesDel_addAF
Benign
-0.0081
T
BayesDel_noAF
Benign
-0.090
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.21
.;T
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Benign
0.027
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.7
.;M
PrimateAI
Pathogenic
0.88
D
PROVEAN
Uncertain
-3.7
D;D
REVEL
Uncertain
0.55
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.014
D;D
Polyphen
1.0
.;D
Vest4
0.82
MutPred
0.70
.;Loss of methylation at R393 (P = 0.1181);
MVP
0.62
MPC
1.2
ClinPred
0.86
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.54
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs771875783; hg19: chr20-48497482; API