17-74769076-C-T

Variant names:

• chr17-74769076-C-T
• rs7420
• NM_004252.5:c.*420C>T

Variant summary

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

The NM_004252.5(NHERF1):​c.*420C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 197,548 control chromosomes in the GnomAD database, including 25,323 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 0.50 (19384 hom., cov: 33)
  • Exomes 𝑓: 0.51 (5939 hom.)
• Consequence: NHERF1 NM_004252.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.392
• Publications: 20 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHERF1	NM_004252.5	c.*420C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000262613.10	NP_004243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHERF1	ENST00000262613.10	c.*420C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_004252.5	ENSP00000262613.5
NHERF1	ENST00000413388.2	c.*420C>T		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000464982.1

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76188 AN: 152074 Hom.: 19336 Cov.: 33

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.483

GnomAD4 exome AF: 0.507 AC: 22990 AN: 45356 Hom.: 5939 Cov.: 0 AF XY: 0.505 AC XY: 11723 AN XY: 23198

African (AFR) AF: 0.467 AC: 438 AN: 938

American (AMR) AF: 0.553 AC: 1743 AN: 3150

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 607 AN: 1258

East Asian (EAS) AF: 0.312 AC: 499 AN: 1598

South Asian (SAS) AF: 0.453 AC: 2494 AN: 5506

European-Finnish (FIN) AF: 0.571 AC: 1337 AN: 2342

Middle Eastern (MID) AF: 0.378 AC: 68 AN: 180

European-Non Finnish (NFE) AF: 0.521 AC: 14517 AN: 27874

Other (OTH) AF: 0.513 AC: 1287 AN: 2510

GnomAD4 genome AF: 0.501 AC: 76290 AN: 152192 Hom.: 19384 Cov.: 33 AF XY: 0.502 AC XY: 37329 AN XY: 74400

African (AFR) AF: 0.478 AC: 19827 AN: 41520

American (AMR) AF: 0.521 AC: 7961 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1723 AN: 3470

East Asian (EAS) AF: 0.306 AC: 1584 AN: 5180

South Asian (SAS) AF: 0.434 AC: 2088 AN: 4812

European-Finnish (FIN) AF: 0.554 AC: 5869 AN: 10602

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.526 AC: 35786 AN: 67998

Other (OTH) AF: 0.488 AC: 1030 AN: 2112

Alfa AF: 0.512 Hom.: 55911

Bravo AF: 0.501

Asia WGS AF: 0.381 AC: 1328 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.49
PhyloP100		-0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7420; hg19: chr17-72765215; COSMIC: COSV52853213; COSMIC: COSV52853213;