18-21515583-G-A

Position:

• chr18-21515583-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001142966.3(GREB1L):​c.5068G>A​(p.Val1690Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,399,378 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GREB1L NM_001142966.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 4.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.3236959).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GREB1L	NM_001142966.3	c.5068G>A	p.Val1690Met	missense_variant	29/33	ENST00000424526.7	NP_001136438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GREB1L	ENST00000424526.7	c.5068G>A	p.Val1690Met	missense_variant	29/33	5	NM_001142966.3	ENSP00000412060.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399378 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal hypodysplasia/aplasia 3 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 28, 2020	The heterozygous p.Val1690Met variant in GREB1L was identified by our study in 2 siblings with renal hypodysplasia/aplasia 3 as well as their father whose affection status is unknown. The p.Val1690Met variant in GREB1L has been reported in 4 individuals with renal hypodysplasia/aplasia 3, segregated with disease in these 4 affected relatives from 2 families (PMID: 29100090, 30143558), and was absent from large population studies. This variant has also been reported in ClinVar as Pathogenic by OMIM (Variation ID# 453278). Animal models in zebrafish have shown that this variant causes renal hypodysplasia/aplasia 3 (PMID: 29100090). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The number of missense variants reported in GREB1L in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3, PM2, PP2, BP4, PS4_supporting (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 18, 2017	- -

Congenital anomaly of kidney and urinary tract Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Aug 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;.;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.7	L;.;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N;N;.
REVEL	Benign	0.12
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.98	D;.;D
Vest4		0.38
MutPred		0.24		Gain of loop (P = 0.069);.;Gain of loop (P = 0.069);
MVP		0.37
ClinPred		0.92	D
GERP RS		6.1
Varity_R		0.19
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555663997; hg19: chr18-19095544;