chr18-21384251-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_001142966.3(GREB1L):​c.203G>T​(p.Arg68Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000143 in 1,551,274 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

GREB1L
NM_001142966.3 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.34
Variant links:
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 Likely_benign. Variant got -6 ACMG points.

PP2
Missense variant in the GREB1L gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 5.3659 (above the threshold of 3.09). Trascript score misZ: 5.6738 (above the threshold of 3.09). GenCC associations: The gene is linked to bilateral renal agenesis, renal hypodysplasia/aplasia 3, renal agenesis, unilateral, hearing loss, autosomal dominant 80.
BP4
Computational evidence support a benign effect (MetaRNN=0.15200263).
BP6
Variant 18-21384251-G-T is Benign according to our data. Variant chr18-21384251-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2432267.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS2
High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GREB1LNM_001142966.3 linkc.203G>T p.Arg68Leu missense_variant Exon 4 of 33 ENST00000424526.7 NP_001136438.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GREB1LENST00000424526.7 linkc.203G>T p.Arg68Leu missense_variant Exon 4 of 33 5 NM_001142966.3 ENSP00000412060.1 Q9C091-1

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152116
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000831
AC:
13
AN:
156492
Hom.:
0
AF XY:
0.0000723
AC XY:
6
AN XY:
82940
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000118
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000198
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000145
AC:
203
AN:
1399040
Hom.:
0
Cov.:
31
AF XY:
0.000116
AC XY:
80
AN XY:
690054
show subpopulations
Gnomad4 AFR exome
AF:
0.0000317
Gnomad4 AMR exome
AF:
0.0000280
Gnomad4 ASJ exome
AF:
0.000159
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000172
Gnomad4 OTH exome
AF:
0.000207
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152234
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000165
Hom.:
0
Bravo
AF:
0.000151
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000807
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 29, 2021- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 27, 2024- -
GREB1L-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 25, 2023The GREB1L c.203G>T variant is predicted to result in the amino acid substitution p.Arg68Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-18964212-G-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0081
T;.;T
Eigen
Benign
0.026
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.85
D;D;.
M_CAP
Benign
0.0070
T
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.20
N;N;N
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-1.7
N;N;.
REVEL
Benign
0.13
Sift
Uncertain
0.011
D;T;.
Sift4G
Benign
0.082
T;T;T
Polyphen
0.49
P;.;P
Vest4
0.53
MVP
0.25
ClinPred
0.086
T
GERP RS
5.0
Varity_R
0.14
gMVP
0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs370589003; hg19: chr18-18964212; API