17-74748659-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004252.5(NHERF1):c.-188G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 577,784 control chromosomes in the GnomAD database, including 51,290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (12925 hom., cov: 33)
  • Exomes 𝑓: 0.42 (38365 hom.)
• Consequence: NHERF1 NM_004252.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.91

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]

MIR3615 (HGNC:38905): (microRNA 3615) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

SLC9A3R1-AS1 (HGNC:55322): (SLC9A3R1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-74748659-G-C is Benign according to our data. Variant chr17-74748659-G-C is described in ClinVar as [Benign]. Clinvar id is 1277585.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHERF1	NM_004252.5	c.-188G>C		5_prime_UTR_variant	1/6	ENST00000262613.10
MIR3615	NR_037409.1	n.47G>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHERF1	ENST00000262613.10	c.-188G>C		5_prime_UTR_variant	1/6	1	NM_004252.5	P1
MIR3615	ENST00000581999.1	n.47G>C		non_coding_transcript_exon_variant	1/1
SLC9A3R1-AS1	ENST00000585285.1	n.254C>G		non_coding_transcript_exon_variant	1/2	3
NHERF1	ENST00000583369.5	c.-188G>C		5_prime_UTR_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62075 AN: 151938 Hom.: 12896 Cov.: 33

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.400

GnomAD3 exomes AF: 0.443 AC: 15368 AN: 34686 Hom.: 3510 AF XY: 0.438 AC XY: 7805 AN XY: 17814

Gnomad AFR exome AF: 0.356

Gnomad AMR exome AF: 0.505

Gnomad ASJ exome AF: 0.377

Gnomad EAS exome AF: 0.481

Gnomad SAS exome AF: 0.378

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.427

Gnomad OTH exome AF: 0.449

GnomAD4 exome AF: 0.422 AC: 179552 AN: 425732 Hom.: 38365 Cov.: 4 AF XY: 0.418 AC XY: 93368 AN XY: 223426

Gnomad4 AFR exome AF: 0.366

Gnomad4 AMR exome AF: 0.505

Gnomad4 ASJ exome AF: 0.391

Gnomad4 EAS exome AF: 0.426

Gnomad4 SAS exome AF: 0.371

Gnomad4 FIN exome AF: 0.415

Gnomad4 NFE exome AF: 0.430

Gnomad4 OTH exome AF: 0.418

GnomAD4 genome AF: 0.409 AC: 62151 AN: 152052 Hom.: 12925 Cov.: 33 AF XY: 0.409 AC XY: 30433 AN XY: 74344

Gnomad4 AFR AF: 0.356

Gnomad4 AMR AF: 0.458

Gnomad4 ASJ AF: 0.391

Gnomad4 EAS AF: 0.455

Gnomad4 SAS AF: 0.367

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.405

Alfa AF: 0.418 Hom.: 1812

Bravo AF: 0.415

Asia WGS AF: 0.383 AC: 1330 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.47
Dann	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs745666; hg19: chr17-72744798;