chr17-74748804-C-A

Variant names:

• chr17-74748804-C-A
• rs147405067
• NM_004252.5:c.-43C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004252.5(NHERF1):​c.-43C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,531,540 control chromosomes in the GnomAD database, including 190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (10 hom., cov: 33)
  • Exomes 𝑓: 0.014 (180 hom.)
• Consequence: NHERF1 NM_004252.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.204

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]

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

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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-74748804-C-A is Benign according to our data. Variant chr17-74748804-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1316123.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00787 (1198/152272) while in subpopulation SAS AF = 0.0188 (91/4830). AF 95% confidence interval is 0.0157. There are 10 homozygotes in GnomAd4. There are 542 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1198 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHERF1	NM_004252.5	c.-43C>A		5_prime_UTR_variant	Exon 1 of 6	ENST00000262613.10	NP_004243.1
SLC9A3R1-AS1	NR_187307.1	n.929G>T		non_coding_transcript_exon_variant	Exon 2 of 3
MIR3615	NR_037409.1	n.*105C>A		downstream_gene_variant
MIR3615	unassigned_transcript_3091	n.*121C>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHERF1	ENST00000262613	c.-43C>A		5_prime_UTR_variant	Exon 1 of 6	1	NM_004252.5	ENSP00000262613.5
NHERF1	ENST00000583369	c.-43C>A		5_prime_UTR_variant	Exon 1 of 3	3		ENSP00000464321.1
SLC9A3R1-AS1	ENST00000585285.1	n.109G>T		non_coding_transcript_exon_variant	Exon 1 of 2	3
MIR3615	ENST00000581999.1	n.*105C>A		downstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.00787 AC: 1197 AN: 152154 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.0104 AC: 1712 AN: 164426 AF XY: 0.0115

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.00574

Gnomad ASJ exome AF: 0.00524

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00247

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.00881

GnomAD4 exome AF: 0.0144 AC: 19909 AN: 1379268 Hom.: 180 Cov.: 27 AF XY: 0.0147 AC XY: 10070 AN XY: 684374

Gnomad4 AFR exome AF: 0.00223 AC: 72 AN: 32288

Gnomad4 AMR exome AF: 0.00591 AC: 227 AN: 38378

Gnomad4 ASJ exome AF: 0.00629 AC: 158 AN: 25108

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 37956

Gnomad4 SAS exome AF: 0.0200 AC: 1618 AN: 81028

Gnomad4 FIN exome AF: 0.00307 AC: 108 AN: 35146

Gnomad4 NFE exome AF: 0.0160 AC: 17074 AN: 1066032

Gnomad4 Remaining exome AF: 0.0105 AC: 608 AN: 57710

GnomAD4 genome AF: 0.00787 AC: 1198 AN: 152272 Hom.: 10 Cov.: 33 AF XY: 0.00728 AC XY: 542 AN XY: 74456

Gnomad4 AFR AF: 0.00255 AC: 0.00255004 AN: 0.00255004

Gnomad4 AMR AF: 0.00483 AC: 0.00483471 AN: 0.00483471

Gnomad4 ASJ AF: 0.00519 AC: 0.00518732 AN: 0.00518732

Gnomad4 EAS AF: 0.000194 AC: 0.000193798 AN: 0.000193798

Gnomad4 SAS AF: 0.0188 AC: 0.0188406 AN: 0.0188406

Gnomad4 FIN AF: 0.00226 AC: 0.00225946 AN: 0.00225946

Gnomad4 NFE AF: 0.0128 AC: 0.0128096 AN: 0.0128096

Gnomad4 OTH AF: 0.00567 AC: 0.00567108 AN: 0.00567108

Alfa AF: 0.00864 Hom.: 2

Bravo AF: 0.00779

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 17, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.2
DANN	Benign	0.84
Mutation Taster		=300/0	polymorphism

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: rs147405067; hg19: chr17-72744943;