rs1555654020

Variant names:

• chr18-21473099-C-T
• rs1555654020
• NM_001142966.3:c.2251C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_001142966.3(GREB1L):​c.2251C>T​(p.Arg751Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R751H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GREB1L NM_001142966.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.15
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-21473100-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1172634.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2841556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREB1L	NM_001142966.3	c.2251C>T	p.Arg751Cys	missense_variant	Exon 16 of 33	ENST00000424526.7	NP_001136438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREB1L	ENST00000424526.7	c.2251C>T	p.Arg751Cys	missense_variant	Exon 16 of 33	5	NM_001142966.3	ENSP00000412060.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal hypodysplasia/aplasia 3 Pathogenic:1

Dec 18, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Apr 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29100091) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	0.0078	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.038	T;.;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;L
PhyloP100		3.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.4	D;D;.
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.33	B;B;B
Vest4		0.68
MutPred		0.43		Loss of MoRF binding (P = 0.0047);.;Loss of MoRF binding (P = 0.0047);
MVP		0.36
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.31
gMVP		0.65
Mutation Taster		=5/95	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: rs1555654020; hg19: chr18-19053060; COSMIC: COSV104580578; COSMIC: COSV104580578;