rs35910969

chr17-74749174-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 12/19 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:6
• Conservation: PhyloP100: -0.0950

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 -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. This position pass quality control queck.
• BS2: High AC in GnomAd at 2460 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHERF1	NM_004252.5	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	c.328C>G	p.Leu110Val	missense_variant	1/6	1	NM_004252.5	P1
NHERF1	ENST00000583369.5	c.328C>G	p.Leu110Val	missense_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2460 AN: 152030 Hom.: 33 Cov.: 32

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.: 20 AF XY: 0.0146 AC XY: 1049 AN XY: 71744

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.: 32 AF XY: 0.0254 AC XY: 17319 AN XY: 680916

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.: 33 Cov.: 32 AF XY: 0.0150 AC XY: 1119 AN XY: 74402

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.: 3

Bravo AF: 0.0161

TwinsUK AF: 0.0305 AC: 113

ALSPAC AF: 0.0345 AC: 133

ESP6500AA AF: 0.00403 AC: 14

ESP6500EA AF: 0.0190 AC: 137

ExAC AF: 0.00869 AC: 826

Asia WGS AF: 0.00231 AC: 8 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

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) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NHERF1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypophosphatemic nephrolithiasis/osteoporosis 2 Pathogenic:1 Uncertain:1 Benign: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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	17
Dann	Benign	0.91
DEOGEN2	Benign	0.022	T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.68	A
PrimateAI	Uncertain	0.69	T
Sift4G	Benign	0.27	T;T
Polyphen		0.073	.;B
Vest4		0.13
MPC		0.96
ClinPred		0.0061	T
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

Other links and lift over

dbSNP: rs35910969; hg19: chr17-72745313; COSMIC: COSV99380087; COSMIC: COSV99380087;