rs35910969

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004252.5(NHERF1):c.328C>G(p.Leu110Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,533,822 control chromosomes in the GnomAD database, including 619 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L110L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 33 hom., cov: 32)

Exomes 𝑓: 0.026 ( 586 hom. )

Consequence

NHERF1
NM_004252.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: -0.0950

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003754735).

BP6

Variant 17-74749174-C-G is Benign according to our data. Variant chr17-74749174-C-G is described in ClinVar as [Benign]. Clinvar id is 5270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-74749174-C-G is described in Lovd as [Benign]. Variant chr17-74749174-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0162 (2460/152148) while in subpopulation NFE AF = 0.0279 (1896/67972). AF 95% confidence interval is 0.0268. There are 33 homozygotes in GnomAd4. There are 1119 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 2460 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHERF1	NM_004252.5 link	c.328C>G	p.Leu110Val	missense_variant	Exon 1 of 6	ENST00000262613.10	NP_004243.1	O14745-1
SLC9A3R1-AS1	NR_187307.1 link	n.694G>C		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHERF1	ENST00000262613.10 link	c.328C>G	p.Leu110Val	missense_variant	Exon 1 of 6	1	NM_004252.5	ENSP00000262613.5		O14745-1
NHERF1	ENST00000583369.5 link	c.328C>G	p.Leu110Val	missense_variant	Exon 1 of 3	3		ENSP00000464321.1		J3QRP6

Frequencies

GnomAD3 genomes

AF:

0.0162

AC:

2460

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00529

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.00903

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.00333

Gnomad FIN

AF:

0.00858

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0279

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0148

AC:

1929

AN:

130476

AF XY:

0.0146

show subpopulations

Gnomad AFR exome

AF:

0.00416

Gnomad AMR exome

AF:

0.00616

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.0000941

Gnomad FIN exome

AF:

0.00713

Gnomad NFE exome

AF:

0.0291

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.0263

AC:

36341

AN:

1381674

Hom.:

586

Cov.:

AF XY:

0.0254

AC XY:

17319

AN XY:

680916

show subpopulations

Gnomad4 AFR exome

AF:

0.00439

AC:

138

AN:

31434

Gnomad4 AMR exome

AF:

0.00705

AC:

246

AN:

34880

Gnomad4 ASJ exome

AF:

0.0133

AC:

331

AN:

24896

Gnomad4 EAS exome

AF:

0.0000277

AC:

AN:

36082

Gnomad4 SAS exome

AF:

0.00562

AC:

446

AN:

79302

Gnomad4 FIN exome

AF:

0.00950

AC:

343

AN:

36102

Gnomad4 NFE exome

AF:

0.0311

AC:

33486

AN:

1076058

Gnomad4 Remaining exome

AF:

0.0229

AC:

1319

AN:

57546

Heterozygous variant carriers

2134

4269

6403

8538

10672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

1306

2612

3918

5224

6530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0162

AC:

2460

AN:

152148

Hom.:

Cov.:

AF XY:

0.0150

AC XY:

1119

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00527

AC:

0.00527279

AN:

0.00527279

Gnomad4 AMR

AF:

0.00902

AC:

0.00902197

AN:

0.00902197

Gnomad4 ASJ

AF:

0.0147

AC:

0.0147144

AN:

0.0147144

Gnomad4 EAS

AF:

0.000389

AC:

0.000388651

AN:

0.000388651

Gnomad4 SAS

AF:

0.00333

AC:

0.00332779

AN:

0.00332779

Gnomad4 FIN

AF:

0.00858

AC:

0.0085752

AN:

0.0085752

Gnomad4 NFE

AF:

0.0279

AC:

0.0278938

AN:

0.0278938

Gnomad4 OTH

AF:

0.0118

AC:

0.0118483

AN:

0.0118483

Heterozygous variant carriers

118

236

354

472

590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0198

Hom.:

Bravo

AF:

0.0161

TwinsUK

AF:

0.0305

AC:

113

ALSPAC

AF:

0.0345

AC:

133

ESP6500AA

AF:

0.00403

AC:

ESP6500EA

AF:

0.0190

AC:

137

ExAC

AF:

0.00869

AC:

826

Asia WGS

AF:

0.00231

AC:

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NHERF1: BS1, BS2 -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 15, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31672324, 18784102, 26787776, 25333069, 22995991, 31171716, 29275531) -

Hypophosphatemic nephrolithiasis/osteoporosis 2

Pathogenic:1Benign:2

Sep 11, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant NM_004252.5(NHERF1):c.328C>G (p.Leu110Val) is an old submission that was updated given new versions of GnomAD. It has GnomAD 4.1.0 frequency of 0.02530 with 619 homozygotes. It was found internally in patients with different phenotypes explained by other variants. Applied assertion criteria redefined it as Benign. -

not specified

Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.022

T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

.;L

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.86

.;N

REVEL

Benign

0.070

Sift

Benign

0.28

.;T

Sift4G

Benign

0.27

T;T

Polyphen

0.073

.;B

Vest4

0.13

MPC

0.96

ClinPred

0.0061

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.35

Mutation Taster

=74/26

polymorphism

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