18-21384325-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 9.14

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GREB1L
• 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: {Benign=2, Uncertain_significance=1, Likely_benign=1}.
• 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 GnomAd at 469 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 469 AN: 152202 Hom.: 2 Cov.: 32

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.: 0 AF XY: 0.00264 AC XY: 220 AN XY: 83278

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.: 17 Cov.: 31 AF XY: 0.00414 AC XY: 2856 AN XY: 690226

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.: 2 Cov.: 32 AF XY: 0.00289 AC XY: 215 AN XY: 74484

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.: 0

Bravo AF: 0.00300

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00534 AC: 17

ExAC AF: 0.00206 AC: 52

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	GREB1L: PP2, BS1 -

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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.35
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.011	T;.;T
Eigen	Uncertain	0.58
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;.
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Uncertain	0.54	T
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	T
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

Other links and lift over

dbSNP: rs185578147; hg19: chr18-18964286; COSMIC: COSV104580625;