1-27100483-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_003047.5(SLC9A1):​c.2272G>A​(p.Asp758Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D758D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

SLC9A1
NM_003047.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.11
Variant links:
Genes affected
SLC9A1 (HGNC:11071): (solute carrier family 9 member A1) This gene encodes a Na+/H+ antiporter that is a member of the solute carrier family 9. The encoded protein is a plasma membrane transporter that is expressed in the kidney and intestine. This protein plays a central role in regulating pH homeostasis, cell migration and cell volume. This protein may also be involved in tumor growth. [provided by RefSeq, Sep 2011]

Genome browser will be placed here

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;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC9A1. . Gene score misZ 3.5504 (greater than the threshold 3.09). Trascript score misZ 4.6807 (greater than threshold 3.09). GenCC has associacion of gene with Lichtenstein-Knorr syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.087812066).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC9A1NM_003047.5 linkuse as main transcriptc.2272G>A p.Asp758Asn missense_variant 12/12 ENST00000263980.8 NP_003038.2 P19634-1B2RAH2
SLC9A1XM_011542021.4 linkuse as main transcriptc.1942G>A p.Asp648Asn missense_variant 13/13 XP_011540323.1
SLC9A1XM_047428769.1 linkuse as main transcriptc.1942G>A p.Asp648Asn missense_variant 16/16 XP_047284725.1
SLC9A1NR_046474.2 linkuse as main transcriptn.2602G>A non_coding_transcript_exon_variant 11/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC9A1ENST00000263980.8 linkuse as main transcriptc.2272G>A p.Asp758Asn missense_variant 12/121 NM_003047.5 ENSP00000263980.3 P19634-1
SLC9A1ENST00000374089.5 linkuse as main transcriptn.1497G>A non_coding_transcript_exon_variant 7/72
SLC9A1ENST00000447808.1 linkuse as main transcriptn.749G>A non_coding_transcript_exon_variant 6/62

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152212
Hom.:
0
Cov.:
34
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000637
AC:
16
AN:
251366
Hom.:
0
AF XY:
0.0000663
AC XY:
9
AN XY:
135842
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000132
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000177
AC:
259
AN:
1461776
Hom.:
0
Cov.:
39
AF XY:
0.000164
AC XY:
119
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000227
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152212
Hom.:
0
Cov.:
34
AF XY:
0.0000538
AC XY:
4
AN XY:
74372
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:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000137
Hom.:
0
Bravo
AF:
0.0000756
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000273
EpiControl
AF:
0.000178

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 06, 2021The c.2272G>A (p.D758N) alteration is located in exon 12 (coding exon 12) of the SLC9A1 gene. This alteration results from a G to A substitution at nucleotide position 2272, causing the aspartic acid (D) at amino acid position 758 to be replaced by an asparagine (N). 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
Benign
0.089
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.24
T
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.50
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.67
T
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.088
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
L
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.60
N
REVEL
Benign
0.082
Sift
Benign
0.092
T
Sift4G
Benign
0.36
T
Polyphen
0.19
B
Vest4
0.098
MVP
0.26
MPC
0.25
ClinPred
0.091
T
GERP RS
2.1
Varity_R
0.034
gMVP
0.24

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: rs138525900; hg19: chr1-27426974; COSMIC: COSV56050724; COSMIC: COSV56050724; API