17-74748913-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_004252.5(NHERF1):c.67G>C(p.Gly23Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,601,080 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 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NHERF1
NM_004252.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.14

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]

NHERF1 links:

SLC9A3R1-AS1 (HGNC:55322): (SLC9A3R1 antisense RNA 1)

SLC9A3R1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHERF1	NM_004252.5 link	c.67G>C	p.Gly23Arg	missense_variant	Exon 1 of 6	ENST00000262613.10	NP_004243.1	O14745-1
SLC9A3R1-AS1	NR_187307.1 link	n.820C>G		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NHERF1	ENST00000262613.10 link	c.67G>C	p.Gly23Arg	missense_variant	Exon 1 of 6	1	NM_004252.5	ENSP00000262613.5	O14745-1
NHERF1	ENST00000583369.5 link	c.67G>C	p.Gly23Arg	missense_variant	Exon 1 of 3	3		ENSP00000464321.1	J3QRP6
SLC9A3R1-AS1	ENST00000585285.1 link	n.-1C>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152180

Hom.:

Cov.:

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000441

AC:

AN:

226914

Hom.:

AF XY:

0.00000797

AC XY:

AN XY:

125508

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:

0.00000981

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1448900

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720494

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:

0.0000329

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74338

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 23 of the SLC9A3R1 protein (p.Gly23Arg). This variant is present in population databases (no rsID available, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with SLC9A3R1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Uncertain

2.5

.;M

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.2

.;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

.;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

.;D

Vest4

0.79

MutPred

0.84

Gain of methylation at G23 (P = 0.0531);Gain of methylation at G23 (P = 0.0531);

MVP

0.79

MPC

2.2

ClinPred

1.0

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.87

gMVP

0.88

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over