chr17-74748931-C-A
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_004252.5(NHERF1):c.85C>A(p.His29Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000543 in 1,603,390 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000058 ( 1 hom. )
Consequence
NHERF1
NM_004252.5 missense
NM_004252.5 missense
Scores
3
4
8
Clinical Significance
Conservation
PhyloP100: 4.14
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.09633219).
BP6
Variant 17-74748931-C-A is Benign according to our data. Variant chr17-74748931-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1653202.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2}.
BS2
High AC in GnomAdExome4 at 84 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NHERF1 | NM_004252.5 | c.85C>A | p.His29Asn | missense_variant | 1/6 | ENST00000262613.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NHERF1 | ENST00000262613.10 | c.85C>A | p.His29Asn | missense_variant | 1/6 | 1 | NM_004252.5 | P1 | |
NHERF1 | ENST00000583369.5 | c.85C>A | p.His29Asn | missense_variant | 1/3 | 3 | |||
SLC9A3R1-AS1 | ENST00000585285.1 | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000220 AC: 50AN: 227262Hom.: 1 AF XY: 0.000151 AC XY: 19AN XY: 125634
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GnomAD4 exome AF: 0.0000579 AC: 84AN: 1451244Hom.: 1 Cov.: 32 AF XY: 0.0000416 AC XY: 30AN XY: 721754
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypophosphatemic nephrolithiasis/osteoporosis 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 08, 2021 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jun 29, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;D
Polyphen
1.0
.;D
Vest4
0.59
MutPred
Loss of ubiquitination at K32 (P = 0.1016);Loss of ubiquitination at K32 (P = 0.1016);
MVP
MPC
2.1
ClinPred
T
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at