NM_004252.5:c.96G>C

Variant summary

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

The NM_004252.5(NHERF1):ā€‹c.96G>Cā€‹(p.Lys32Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,604,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

NHERF1
NM_004252.5 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.86
Variant links:
Genes affected
NHERF1 (HGNC:11075): (NHERF family PDZ scaffold protein 1) This gene encodes a sodium/hydrogen exchanger regulatory cofactor. The protein interacts with and regulates various proteins including the cystic fibrosis transmembrane conductance regulator and G-protein coupled receptors such as the beta2-adrenergic receptor and the parathyroid hormone 1 receptor. The protein also interacts with proteins that function as linkers between integral membrane and cytoskeletal proteins. The protein localizes to actin-rich structures including membrane ruffles, microvilli, and filopodia. Mutations in this gene result in hypophosphatemic nephrolithiasis/osteoporosis type 2, and loss of heterozygosity of this gene is implicated in breast cancer.[provided by RefSeq, Sep 2009]
SLC9A3R1-AS1 (HGNC:55322): (SLC9A3R1 antisense RNA 1)

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;
BP4
Computational evidence support a benign effect (MetaRNN=0.2976048).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NHERF1NM_004252.5 linkc.96G>C p.Lys32Asn missense_variant Exon 1 of 6 ENST00000262613.10 NP_004243.1 O14745-1
SLC9A3R1-AS1NR_187307.1 linkn.806-15C>G intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NHERF1ENST00000262613.10 linkc.96G>C p.Lys32Asn missense_variant Exon 1 of 6 1 NM_004252.5 ENSP00000262613.5 O14745-1
NHERF1ENST00000583369.5 linkc.96G>C p.Lys32Asn missense_variant Exon 1 of 3 3 ENSP00000464321.1 J3QRP6
SLC9A3R1-AS1ENST00000585285.1 linkn.-30C>G upstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152198
Hom.:
0
Cov.:
33
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1452628
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
722424
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:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152198
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74354
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Nov 12, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.96G>C (p.K32N) alteration is located in exon 1 (coding exon 1) of the SLC9A3R1 gene. This alteration results from a G to C substitution at nucleotide position 96, causing the lysine (K) at amino acid position 32 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
Pathogenic
0.97
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
23
DANN
Benign
0.92
DEOGEN2
Benign
0.017
T;T
Eigen
Benign
0.16
Eigen_PC
Benign
0.11
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.30
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.82
.;L
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-3.4
.;D
REVEL
Benign
0.17
Sift
Uncertain
0.0010
.;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
.;D
Vest4
0.40
MutPred
0.45
Loss of ubiquitination at K32 (P = 0.0148);Loss of ubiquitination at K32 (P = 0.0148);
MVP
0.52
MPC
2.2
ClinPred
0.98
D
GERP RS
1.2
Varity_R
0.96
gMVP
0.76

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: rs2034819878; hg19: chr17-72745081; API