17-74769076-C-T

Position:

• chr17-74769076-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	Protein	UniProt
NHERF1	NM_004252.5	c.*420C>T		3_prime_UTR_variant	6/6	ENST00000262613.10	NP_004243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHERF1	ENST00000262613.10	c.*420C>T		3_prime_UTR_variant	6/6	1	NM_004252.5	ENSP00000262613.5
NHERF1	ENST00000413388.2	c.*420C>T		3_prime_UTR_variant	5/5	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

Gnomad4 AFR exome AF: 0.467

Gnomad4 AMR exome AF: 0.553

Gnomad4 ASJ exome AF: 0.483

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.453

Gnomad4 FIN exome AF: 0.571

Gnomad4 NFE exome AF: 0.521

Gnomad4 OTH exome AF: 0.513

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

Gnomad4 AFR AF: 0.478

Gnomad4 AMR AF: 0.521

Gnomad4 ASJ AF: 0.497

Gnomad4 EAS AF: 0.306

Gnomad4 SAS AF: 0.434

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.526

Gnomad4 OTH AF: 0.488

Alfa AF: 0.509 Hom.: 25778

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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