rs1163868389

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004252.5(NHERF1):​c.44G>A​(p.Cys15Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,446,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NHERF1
NM_004252.5 missense

Scores

8
7
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.85
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NHERF1NM_004252.5 linkc.44G>A p.Cys15Tyr missense_variant Exon 1 of 6 ENST00000262613.10 NP_004243.1 O14745-1
SLC9A3R1-AS1NR_187307.1 linkn.843C>T non_coding_transcript_exon_variant Exon 2 of 3
MIR3615NR_037409.1 linkn.*191G>A downstream_gene_variant
MIR3615unassigned_transcript_3091 n.*207G>A downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NHERF1ENST00000262613.10 linkc.44G>A p.Cys15Tyr missense_variant Exon 1 of 6 1 NM_004252.5 ENSP00000262613.5 O14745-1
NHERF1ENST00000583369.5 linkc.44G>A p.Cys15Tyr missense_variant Exon 1 of 3 3 ENSP00000464321.1 J3QRP6
SLC9A3R1-AS1ENST00000585285.1 linkn.23C>T non_coding_transcript_exon_variant Exon 1 of 2 3
MIR3615ENST00000581999.1 linkn.*191G>A downstream_gene_variant 6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1446022
Hom.:
0
Cov.:
32
AF XY:
0.00000278
AC XY:
2
AN XY:
718980
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.01e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
28
DANN
Uncertain
0.98
DEOGEN2
Benign
0.17
T;D
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Benign
-0.57
T
MutationAssessor
Uncertain
2.4
.;M
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-7.0
.;D
REVEL
Uncertain
0.57
Sift
Benign
0.035
.;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
.;D
Vest4
0.71
MutPred
0.52
Loss of ubiquitination at K19 (P = 0.0648);Loss of ubiquitination at K19 (P = 0.0648);
MVP
0.73
MPC
2.6
ClinPred
1.0
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.93
gMVP
0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-72745029; API