rs1555654020
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2PM5PP2BP4
The NM_001142966.3(GREB1L):c.2251C>T(p.Arg751Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R751H) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
GREB1L
NM_001142966.3 missense
NM_001142966.3 missense
Scores
3
5
11
Clinical Significance
Conservation
PhyloP100: 3.15
Genes affected
GREB1L (HGNC:31042): (GREB1 like retinoic acid receptor coactivator) Acts upstream of or within kidney development. Predicted to be integral component of membrane. Implicated in autosomal dominant nonsyndromic deafness and renal agenesis. [provided by Alliance of Genome Resources, Apr 2022]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GREB1L. . Gene score misZ: 5.3659 (greater than the threshold 3.09). Trascript score misZ: 5.6738 (greater than threshold 3.09). The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. GenCC has associacion of the gene with bilateral renal agenesis, renal hypodysplasia/aplasia 3, renal agenesis, unilateral, hearing loss, autosomal dominant 80.
BP4
Computational evidence support a benign effect (MetaRNN=0.2841556).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GREB1L | NM_001142966.3 | c.2251C>T | p.Arg751Cys | missense_variant | 16/33 | ENST00000424526.7 | NP_001136438.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Renal hypodysplasia/aplasia 3 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 18, 2017 | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29100091) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Benign
Sift
Uncertain
D;D;.
Sift4G
Pathogenic
D;D;D
Polyphen
B;B;B
Vest4
MutPred
Loss of MoRF binding (P = 0.0047);.;Loss of MoRF binding (P = 0.0047);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at