18-21496602-C-T

Variant names:

• chr18-21496602-C-T
• rs1555659101
• NM_001142966.3:c.3295C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001142966.3(GREB1L):​c.3295C>T​(p.Gln1099*) variant causes a stop gained change involving the alteration of a non-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 Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GREB1L NM_001142966.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.56
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• renal hypodysplasia/aplasia 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Illumina, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal dominant 80

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-21496602-C-T is Pathogenic according to our data. Variant chr18-21496602-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 453279.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142966.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREB1L	NM_001142966.3	MANE Select	c.3295C>T	p.Gln1099*	stop_gained	Exon 21 of 33	NP_001136438.1
	GREB1L	NM_001410867.1		c.3424C>T	p.Gln1142*	stop_gained	Exon 22 of 34	NP_001397796.1
	GREB1L	NM_001410868.1		c.2968C>T	p.Gln990*	stop_gained	Exon 20 of 32	NP_001397797.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREB1L	ENST00000424526.7	TSL:5 MANE Select	c.3295C>T	p.Gln1099*	stop_gained	Exon 21 of 33	ENSP00000412060.1
	GREB1L	ENST00000579454.2	TSL:5	c.3424C>T	p.Gln1142*	stop_gained	Exon 22 of 34	ENSP00000463926.2
	GREB1L	ENST00000580732.6	TSL:5	c.3295C>T	p.Gln1099*	stop_gained	Exon 21 of 33	ENSP00000464162.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Renal hypodysplasia/aplasia 3 Pathogenic:2

Nov 05, 2024

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

Dec 18, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.75	D
PhyloP100		2.6
Vest4		0.21
GERP RS		3.8
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555659101; hg19: chr18-19076563;