rs1555654020

chr18-21473099-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2 PM5 PP2 PP5 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 Pathogenic (no stars). 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: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.15

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 Uncertain_significance. Variant got 5 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 [Likely_pathogenic]. Clinvar id is 1172634.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, GREB1L
• PP5: Variant 18-21473099-C-T is Pathogenic according to our data. Variant chr18-21473099-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 453284.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-21473099-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2841556).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREB1L	NM_001142966.3	c.2251C>T	p.Arg751Cys	missense_variant	16/33	ENST00000424526.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREB1L	ENST00000424526.7	c.2251C>T	p.Arg751Cys	missense_variant	16/33	5	NM_001142966.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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	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
MutationTaster	Benign	1.0	D;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555654020; hg19: chr18-19053060; COSMIC: COSV104580578; COSMIC: COSV104580578;