5-476619-C-T

Position:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_004174.4(SLC9A3):​c.1814G>A​(p.Arg605Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,609,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

SLC9A3
NM_004174.4 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.52
Variant links:
Genes affected
SLC9A3 (HGNC:11073): (solute carrier family 9 member A3) The protein encoded by this gene is an epithelial brush border Na/H exchanger that uses an inward sodium ion gradient to expel acids from the cell. Defects in this gene are a cause of congenital secretory sodium diarrhea. Pseudogenes of this gene exist on chromosomes 10 and 22. [provided by RefSeq, Mar 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.008811086).
BP6
Variant 5-476619-C-T is Benign according to our data. Variant chr5-476619-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547876.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000197 (30/152342) while in subpopulation EAS AF= 0.00193 (10/5182). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC9A3NM_004174.4 linkuse as main transcriptc.1814G>A p.Arg605Gln missense_variant 12/17 ENST00000264938.8 NP_004165.2 P48764-1
SLC9A3NM_001284351.3 linkuse as main transcriptc.1787G>A p.Arg596Gln missense_variant 12/17 NP_001271280.1 P48764-2
SLC9A3-AS1NR_125375.1 linkuse as main transcriptn.679+56C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC9A3ENST00000264938.8 linkuse as main transcriptc.1814G>A p.Arg605Gln missense_variant 12/171 NM_004174.4 ENSP00000264938.3 P48764-1

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152224
Hom.:
0
Cov.:
34
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:
0.00193
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000267
AC:
66
AN:
246780
Hom.:
0
AF XY:
0.000261
AC XY:
35
AN XY:
134110
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00213
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000196
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000214
AC:
312
AN:
1457244
Hom.:
0
Cov.:
35
AF XY:
0.000214
AC XY:
155
AN XY:
725164
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00136
Gnomad4 SAS exome
AF:
0.000174
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000192
Gnomad4 OTH exome
AF:
0.000348
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152342
Hom.:
0
Cov.:
34
AF XY:
0.000175
AC XY:
13
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00193
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000227
Hom.:
0
Bravo
AF:
0.000215
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000264
AC:
32
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Congenital secretory sodium diarrhea 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicOct 26, 2016- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 09, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.058
.;T;.
Eigen
Benign
0.042
Eigen_PC
Benign
-0.059
FATHMM_MKL
Benign
0.44
N
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.0088
T;T;T
MetaSVM
Benign
-0.49
T
MutationAssessor
Benign
1.6
.;L;.
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
0.10
.;N;N
REVEL
Benign
0.20
Sift
Benign
0.61
.;T;T
Sift4G
Benign
0.50
.;T;T
Polyphen
1.0
.;D;.
Vest4
0.50, 0.50
MVP
0.81
MPC
0.78
ClinPred
0.052
T
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.12
gMVP
0.29

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: rs146547322; hg19: chr5-476734; COSMIC: COSV99376413; COSMIC: COSV99376413; API