rs1555662027

Variant names:

• chr18-21508463-A-G
• rs1555662027
• NM_001142966.3:c.4607A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001142966.3(GREB1L):​c.4607A>G​(p.His1536Arg) 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GREB1L NM_001142966.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.95
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812
• PP5: Variant 18-21508463-A-G is Pathogenic according to our data. Variant chr18-21508463-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 453283.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREB1L	NM_001142966.3	MANE Select	c.4607A>G	p.His1536Arg	missense	Exon 27 of 33	NP_001136438.1	Q9C091-1
	GREB1L	NM_001410867.1		c.4736A>G	p.His1579Arg	missense	Exon 28 of 34	NP_001397796.1	J3QQW0
	GREB1L	NM_001410868.1		c.4280A>G	p.His1427Arg	missense	Exon 26 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.4607A>G	p.His1536Arg	missense	Exon 27 of 33	ENSP00000412060.1	Q9C091-1
	GREB1L	ENST00000861016.1		c.4739A>G	p.His1580Arg	missense	Exon 29 of 35	ENSP00000531075.1
	GREB1L	ENST00000579454.2	TSL:5	c.4736A>G	p.His1579Arg	missense	Exon 28 of 34	ENSP00000463926.2	J3QQW0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Renal hypodysplasia/aplasia 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.052	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.60
Sift	Benign	0.083	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.66		Loss of catalytic residue at M1538 (P = 0.1152)
MVP		0.40
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.54
gMVP		1.0
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: rs1555662027; hg19: chr18-19088424;