chr18-21384325-G-A

Position:

chr18-21384325-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001142966.3(GREB1L):c.277G>A(p.Glu93Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,551,744 control chromosomes in the GnomAD database, including 19 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 0.0031 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 17 hom. )

Consequence

GREB1L
NM_001142966.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 9.14

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]

GREB1L links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

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). GenCC has associacion of 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=0.0039663613).

BP6

Variant 18-21384325-G-A is Benign according to our data. Variant chr18-21384325-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 917910.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00308 (469/152320) while in subpopulation NFE AF= 0.00501 (341/68030). AF 95% confidence interval is 0.00457. There are 2 homozygotes in gnomad4. There are 215 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 469 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GREB1L	NM_001142966.3 linkuse as main transcript	c.277G>A	p.Glu93Lys	missense_variant	4/33	ENST00000424526.7	NP_001136438.1
LOC101927521	XR_001753366.2 linkuse as main transcript	n.245-3650C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GREB1L	ENST00000424526.7 linkuse as main transcript	c.277G>A	p.Glu93Lys	missense_variant	4/33	5	NM_001142966.3	ENSP00000412060		Q9C091-1
	ENST00000584611.1 linkuse as main transcript	n.289+3188C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00308

AC:

469

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00501

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00260

AC:

410

AN:

157698

Hom.:

AF XY:

0.00264

AC XY:

220

AN XY:

83278

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00239

Gnomad ASJ exome

AF:

0.00270

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000307

Gnomad FIN exome

AF:

0.00112

Gnomad NFE exome

AF:

0.00460

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00427

AC:

5976

AN:

1399424

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

2856

AN XY:

690226

show subpopulations

Gnomad4 AFR exome

AF:

0.000855

Gnomad4 AMR exome

AF:

0.00235

Gnomad4 ASJ exome

AF:

0.00294

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.000189

Gnomad4 FIN exome

AF:

0.00140

Gnomad4 NFE exome

AF:

0.00506

Gnomad4 OTH exome

AF:

0.00387

GnomAD4 genome

AF:

0.00308

AC:

469

AN:

152320

Hom.:

Cov.:

AF XY:

0.00289

AC XY:

215

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000938

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00501

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00454

Hom.:

Bravo

AF:

0.00300

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00534

AC:

ExAC

AF:

0.00206

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	GREB1L: PP2, BS1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mayer-Rokitansky-Kuster-Hauser syndrome;C4540497:Renal hypodysplasia/aplasia 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Human Genetic Laboratory, University of Liege

Feb 20, 2020

The variant is in a gene (GREB1L) previously associated with renal and uterine malformations in human.The variant is reported in Gnomad with a MAF:0.002813 and is reported once at a homozygous state. The variant affects a moderately conserved nucleotide and poorly conserved aminoacid. In silico prediction are conflicting. We have identified this heterozygous variant in one individual with MRKH syndrome type 1 (sequencing not performed in the parents); one individual with MRKH type 2, mild caliectasis, vertebral anomalies and imperforate anus (sequencing not performed in the parents); and in two fetuses with uterovaginal aplasia, bilateral renal agenesis, ureter and bladder agenesis as well as their asymptomatic father (in cis with the variant c.3970-20A>G in GREB1L). -

GREB1L-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

T;.;T

Eigen

Uncertain

0.58

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;.

M_CAP

Benign

0.0058

MetaRNN

Benign

0.0040

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;L

MutationTaster

Benign

1.0

D;D;D;D;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.2

N;N;.

REVEL

Benign

0.20

Sift

Uncertain

0.0050

D;D;.

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

0.87

P;.;P

Vest4

0.28

MVP

0.20

ClinPred

0.024

GERP RS

5.3

Varity_R

0.31

gMVP

0.43

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over