rs119486097

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004252.5(NHERF1):c.673G>A(p.Glu225Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00308 in 1,614,038 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E225Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 22 hom. )

Consequence

NHERF1
NM_004252.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2B:5

Conservation

PhyloP100: 4.63

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

hypophosphatemic nephrolithiasis/osteoporosis 2
Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
dominant hypophosphatemia with nephrolithiasis or osteoporosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NHERF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007968813).

BP6

Variant 17-74763436-G-A is Benign according to our data. Variant chr17-74763436-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 5272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 510 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHERF1	NM_004252.5 link	c.673G>A	p.Glu225Lys	missense_variant	Exon 3 of 6	ENST00000262613.10	NP_004243.1	O14745-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHERF1	ENST00000262613.10 link	c.673G>A	p.Glu225Lys	missense_variant	Exon 3 of 6	1	NM_004252.5	ENSP00000262613.5		O14745-1

Frequencies

GnomAD3 genomes

AF:

0.00335

AC:

510

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0205

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00378

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00344

AC:

859

AN:

249956

AF XY:

0.00319

show subpopulations

Gnomad AFR exome

AF:

0.000559

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.00328

Gnomad OTH exome

AF:

0.00476

GnomAD4 exome

AF:

0.00305

AC:

4455

AN:

1461652

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

2206

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33476

American (AMR)

AF:

0.000448

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.0199

AC:

1064

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00287

AC:

3189

AN:

1111924

Other (OTH)

AF:

0.00270

AC:

163

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

236

472

707

943

1179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00335

AC:

510

AN:

152386

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41592

American (AMR)

AF:

0.000522

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0205

AC:

218

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00378

AC:

257

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00270

Hom.:

Bravo

AF:

0.00165

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00325

AC:

394

EpiCase

AF:

0.00224

EpiControl

AF:

0.00291

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NHERF1: BP4, BS1, BS2 -

Hypophosphatemic nephrolithiasis/osteoporosis 2

Pathogenic:1

Sep 11, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hypophosphatemia;C0392525:Nephrolithiasis

Pathogenic:1

Sep 08, 2017

Yale Center for Mendelian Genomics, Yale University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene has limited evidence for disease association. Variant reported in a patient with renal calcium lithiasis (Karim 2008), and one with Nephrolithiasis/Nephrocalcinosis (heterozygous, only variant in both cases. Gene is linlked to AD Nephrolithiasis) (Halbritter 2015). Frequency 2.2%. -

NHERF1-related disorder

Benign:1

Dec 08, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Dominant hypophosphatemia with nephrolithiasis or osteoporosis

Benign:1

Sep 02, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.070

Eigen_PC

Benign

0.039

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.85

T;D

MetaRNN

Benign

0.0080

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;.

PhyloP100

4.6

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.5

D;.

REVEL

Benign

0.20

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.014

D;D

Polyphen

0.98

D;.

Vest4

0.61

MVP

0.26

MPC

0.33

ClinPred

0.046

GERP RS

4.5

Varity_R

0.79

gMVP

0.62

Mutation Taster

=56/44

polymorphism

(source)

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

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rs119486097

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over