17-74769592-G-A

Variant names:

• chr17-74769592-G-A
• rs734232
• NM_004252.5:c.*936G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004252.5(NHERF1):​c.*936G>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 152,080 control chromosomes in the GnomAD database, including 10,224 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (10224 hom., cov: 32)
• Consequence: NHERF1 NM_004252.5 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.110
• Publications: 10 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004252.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHERF1	NM_004252.5	MANE Select	c.*936G>A		downstream_gene	N/A	NP_004243.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHERF1	ENST00000262613.10	TSL:1 MANE Select	c.*936G>A		downstream_gene	N/A	ENSP00000262613.5

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51295 AN: 151962 Hom.: 10222 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.337

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.337 AC: 51301 AN: 152080 Hom.: 10224 Cov.: 32 AF XY: 0.339 AC XY: 25162 AN XY: 74316

African (AFR) AF: 0.123 AC: 5094 AN: 41526

American (AMR) AF: 0.345 AC: 5264 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 1429 AN: 3470

East Asian (EAS) AF: 0.266 AC: 1373 AN: 5160

South Asian (SAS) AF: 0.371 AC: 1789 AN: 4824

European-Finnish (FIN) AF: 0.460 AC: 4849 AN: 10548

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.448 AC: 30435 AN: 67972

Other (OTH) AF: 0.342 AC: 720 AN: 2106

Alfa AF: 0.393 Hom.: 5224

Bravo AF: 0.321

Asia WGS AF: 0.301 AC: 1050 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.0
DANN	Benign	0.71
PhyloP100		-0.11

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs734232; hg19: chr17-72765731;