rs1555664772

Variant names:

• chr18-21518140-T-G
• rs1555664772
• NM_001142966.3:c.5378T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM2 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 (★). ClinVar reports functional evidence for this variant: "SCV004296909: Experimental studies have shown that this missense change affects GREB1L function (PMID:28739660).".

• 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
• 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004296909: Experimental studies have shown that this missense change affects GREB1L function (PMID: 28739660).
• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 453273.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREB1L	NM_001142966.3	MANE Select	c.5378T>G	p.Leu1793Arg	missense	Exon 31 of 33	NP_001136438.1	Q9C091-1
	GREB1L	NM_001410867.1		c.5507T>G	p.Leu1836Arg	missense	Exon 32 of 34	NP_001397796.1	J3QQW0
	GREB1L	NM_001410868.1		c.5051T>G	p.Leu1684Arg	missense	Exon 30 of 32	NP_001397797.1	Q9C091-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREB1L	ENST00000424526.7	TSL:5 MANE Select	c.5378T>G	p.Leu1793Arg	missense	Exon 31 of 33	ENSP00000412060.1	Q9C091-1
	GREB1L	ENST00000861016.1		c.5510T>G	p.Leu1837Arg	missense	Exon 33 of 35	ENSP00000531075.1
	GREB1L	ENST00000579454.2	TSL:5	c.5507T>G	p.Leu1836Arg	missense	Exon 32 of 34	ENSP00000463926.2	J3QQW0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Renal hypodysplasia/aplasia 3 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.56		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555664772; hg19: chr18-19098101;