rs119486097

chr17-74763436-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (22 hom.)
• Consequence: NHERF1 NM_004252.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 B:4
• Conservation: PhyloP100: 4.63

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]

ACMG classification

Verdict is Benign. Variant got -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 GnomAd at 510 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHERF1	NM_004252.5	c.673G>A	p.Glu225Lys	missense_variant	3/6	ENST00000262613.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHERF1	ENST00000262613.10	c.673G>A	p.Glu225Lys	missense_variant	3/6	1	NM_004252.5	P1

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 510 AN: 152268 Hom.: 3 Cov.: 33

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

GnomAD3 exomes AF: 0.00344 AC: 859 AN: 249956 Hom.: 5 AF XY: 0.00319 AC XY: 432 AN XY: 135350

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 SAS exome AF: 0.0000327

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.: 22 Cov.: 31 AF XY: 0.00303 AC XY: 2206 AN XY: 727114

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.00287

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00335 AC: 510 AN: 152386 Hom.: 3 Cov.: 33 AF XY: 0.00388 AC XY: 289 AN XY: 74514

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000522

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0205

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00277 Hom.: 1

Bravo AF: 0.00165

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00325 AC: 394

EpiCase AF: 0.00224

EpiControl AF: 0.00291

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	NHERF1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 05, 2023	- -

Hypophosphatemic nephrolithiasis/osteoporosis 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 11, 2008

- -

Hypophosphatemia;C0392525:Nephrolithiasis Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Sep 08, 2017

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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 condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 08, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.070
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T;D
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.46	T
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	T
GERP RS		4.5
Varity_R		0.79
gMVP		0.62

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

Other links and lift over

dbSNP: rs119486097; hg19: chr17-72759575;