Genetic Variant NHERF1:c.-75G>A (chr17-74748772-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004252.5(NHERF1):c.-75G>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 0.0271 in 1,335,408 control chromosomes in the GnomAD database, including 638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.021 ( 49 hom., cov: 33)

Exomes 𝑓: 0.028 ( 589 hom. )

Consequence

NHERF1
NM_004252.5 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.497

Publications

5 publications found

Variant links:

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 links:

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

SLC9A3R1-AS1 links:

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]

MIR3615 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 17-74748772-G-A is Benign according to our data. Variant chr17-74748772-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1315840.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.021 (3201/152254) while in subpopulation NFE AF = 0.0323 (2197/67990). AF 95% confidence interval is 0.0312. There are 49 homozygotes in GnomAd4. There are 1480 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 3201 AD,Unknown gene.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NHERF1	NM_004252.5	MANE Select	c.-75G>A	5_prime_UTR	Exon 1 of 6	NP_004243.1	O14745-1
SLC9A3R1-AS1	NR_187307.1		n.961C>T	non_coding_transcript_exon	Exon 2 of 3
MIR3615	NR_037409.1		n.*73G>A	downstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NHERF1	ENST00000262613.10	TSL:1 MANE Select	c.-75G>A	5_prime_UTR	Exon 1 of 6	ENSP00000262613.5	O14745-1
NHERF1	ENST00000851804.1		c.-75G>A	5_prime_UTR	Exon 1 of 7	ENSP00000521863.1
NHERF1	ENST00000851803.1		c.-75G>A	5_prime_UTR	Exon 1 of 6	ENSP00000521862.1

Frequencies

GnomAD3 genomes

AF:

0.0210

AC:

3202

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00591

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0246

Gnomad ASJ

AF:

0.0550

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.00942

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0323

Gnomad OTH

AF:

0.0210

GnomAD4 exome

AF:

0.0279

AC:

32978

AN:

1183154

Hom.:

589

Cov.:

AF XY:

0.0275

AC XY:

16148

AN XY:

587336

show subpopulations

African (AFR)

AF:

0.00520

AC:

141

AN:

27136

American (AMR)

AF:

0.0174

AC:

544

AN:

31314

Ashkenazi Jewish (ASJ)

AF:

0.0566

AC:

1310

AN:

23142

East Asian (EAS)

AF:

0.000202

AC:

AN:

34658

South Asian (SAS)

AF:

0.00789

AC:

590

AN:

74758

European-Finnish (FIN)

AF:

0.0132

AC:

438

AN:

33160

Middle Eastern (MID)

AF:

0.0227

AC:

120

AN:

5298

European-Non Finnish (NFE)

AF:

0.0315

AC:

28487

AN:

903078

Other (OTH)

AF:

0.0265

AC:

1341

AN:

50610

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

1603

3206

4808

6411

8014

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1034

2068

3102

4136

5170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0210

AC:

3201

AN:

152254

Hom.:

Cov.:

AF XY:

0.0199

AC XY:

1480

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00589

AC:

245

AN:

41572

American (AMR)

AF:

0.0246

AC:

376

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0550

AC:

191

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5148

South Asian (SAS)

AF:

0.00476

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00942

AC:

100

AN:

10616

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0323

AC:

2197

AN:

67990

Other (OTH)

AF:

0.0208

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

161

322

483

644

805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0235

Hom.:

Bravo

AF:

0.0215

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

4.2

(source)

DANN

Benign

0.88

PhyloP100

-0.50

PromoterAI

-0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Mutation Taster

=300/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over