Genetic Variant NHERF1:c.-43C>A (chr17-74748804-C-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.-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

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.204

Publications

1 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 17-74748804-C-A is Benign according to our data. Variant chr17-74748804-C-A is described in ClinVar as Likely_benign. ClinVar VariationId 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 passed quality control check.

BS2

High AC in GnomAd4 at 1198 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.-43C>A	5_prime_UTR	Exon 1 of 6	NP_004243.1	O14745-1
SLC9A3R1-AS1	NR_187307.1		n.929G>T	non_coding_transcript_exon	Exon 2 of 3
MIR3615	NR_037409.1		n.*105C>A	downstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NHERF1	ENST00000262613.10	TSL:1 MANE Select	c.-43C>A	5_prime_UTR	Exon 1 of 6	ENSP00000262613.5	O14745-1
NHERF1	ENST00000851804.1		c.-43C>A	5_prime_UTR	Exon 1 of 7	ENSP00000521863.1
NHERF1	ENST00000851803.1		c.-43C>A	5_prime_UTR	Exon 1 of 6	ENSP00000521862.1

Frequencies

GnomAD3 genomes

AF:

0.00787

AC:

1197

AN:

152154

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0147

AC XY:

10070

AN XY:

684374

show subpopulations

African (AFR)

AF:

0.00223

AC:

AN:

32288

American (AMR)

AF:

0.00591

AC:

227

AN:

38378

Ashkenazi Jewish (ASJ)

AF:

0.00629

AC:

158

AN:

25108

East Asian (EAS)

AF:

0.00

AC:

AN:

37956

South Asian (SAS)

AF:

0.0200

AC:

1618

AN:

81028

European-Finnish (FIN)

AF:

0.00307

AC:

108

AN:

35146

Middle Eastern (MID)

AF:

0.00783

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.0160

AC:

17074

AN:

1066032

Other (OTH)

AF:

0.0105

AC:

608

AN:

57710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

999

1998

2998

3997

4996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

692

1384

2076

2768

3460

<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:

0.00787

AC:

1198

AN:

152272

Hom.:

Cov.:

AF XY:

0.00728

AC XY:

542

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00255

AC:

106

AN:

41568

American (AMR)

AF:

0.00483

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.0188

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0128

AC:

871

AN:

67996

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00864

Hom.:

Bravo

AF:

0.00779

Asia WGS

AF:

0.00635

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

7.2

(source)

DANN

Benign

0.84

PhyloP100

-0.20

PromoterAI

0.095

Neutral

(source)

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

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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