chr17-74749174-C-G

Position:

chr17-74749174-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:6

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5270.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}. 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2460 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHERF1	NM_004252.5 linkuse as main transcript	c.328C>G	p.Leu110Val	missense_variant	1/6	ENST00000262613.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHERF1	ENST00000262613.10 linkuse as main transcript	c.328C>G	p.Leu110Val	missense_variant	1/6	1	NM_004252.5	P1	O14745-1
NHERF1	ENST00000583369.5 linkuse as main transcript	c.328C>G	p.Leu110Val	missense_variant	1/3	3

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

GnomAD3 exomes

AF:

0.0148

AC:

1929

AN:

130476

Hom.:

AF XY:

0.0146

AC XY:

1049

AN XY:

71744

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 SAS exome

AF:

0.00479

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

Gnomad4 AMR exome

AF:

0.00705

Gnomad4 ASJ exome

AF:

0.0133

Gnomad4 EAS exome

AF:

0.0000277

Gnomad4 SAS exome

AF:

0.00562

Gnomad4 FIN exome

AF:

0.00950

Gnomad4 NFE exome

AF:

0.0311

Gnomad4 OTH exome

AF:

0.0229

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

Gnomad4 AMR

AF:

0.00902

Gnomad4 ASJ

AF:

0.0147

Gnomad4 EAS

AF:

0.000389

Gnomad4 SAS

AF:

0.00333

Gnomad4 FIN

AF:

0.00858

Gnomad4 NFE

AF:

0.0279

Gnomad4 OTH

AF:

0.0118

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2019	This variant is associated with the following publications: (PMID: 31672324, 18784102, 26787776, 25333069, 22995991, 31171716, 29275531) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NHERF1: BS1, BS2 -

Hypophosphatemic nephrolithiasis/osteoporosis 2

Pathogenic:1Uncertain:1Benign:1

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 11, 2008	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

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

MutationTaster

Benign

0.68

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

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