rs1555664772

Positions:

• chr18-21518140-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_001142966.3(GREB1L):​c.5378T>G​(p.Leu1793Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GREB1L NM_001142966.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.67

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 Likely_pathogenic. Variant got 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834
• PP5: Variant 18-21518140-T-G is Pathogenic according to our data. Variant chr18-21518140-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 453273.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GREB1L	NM_001142966.3	c.5378T>G	p.Leu1793Arg	missense_variant	31/33	ENST00000424526.7	NP_001136438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GREB1L	ENST00000424526.7	c.5378T>G	p.Leu1793Arg	missense_variant	31/33	5	NM_001142966.3	ENSP00000412060

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 07, 2023

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1793 of the GREB1L protein (p.Leu1793Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with renal agenesis (PMID: 28739660). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 453273). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GREB1L function (PMID: 28739660). For these reasons, this variant has been classified as Pathogenic. -

Renal hypodysplasia/aplasia 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.0	M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.4	D;D;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.78
MutPred		0.56		Gain of solvent accessibility (P = 0.0171);.;Gain of solvent accessibility (P = 0.0171);
MVP		0.68
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.86
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555664772; hg19: chr18-19098101;