Genetic Variant GREB1L:p.Ala6Thr (chr18-21383534-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_001142966.3(GREB1L):c.16G>A(p.Ala6Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000704 in 1,420,280 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000061 ( 0 hom. )

Consequence

GREB1L
NM_001142966.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 7.70

Variant links:

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 links:

ENSG00000265751 (HGNC:58310):

ENSG00000265751 links:

LOC101927521 (HGNC:):

LOC101927521 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in the GREB1L gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 5.3659 (above the threshold of 3.09). Trascript score misZ: 5.6738 (above the threshold of 3.09). GenCC associations: The gene is linked to bilateral renal agenesis, renal hypodysplasia/aplasia 3, renal agenesis, unilateral, hearing loss, autosomal dominant 80.

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREB1L	NM_001142966.3 link	c.16G>A	p.Ala6Thr	missense_variant	Exon 3 of 33	ENST00000424526.7	NP_001136438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREB1L	ENST00000424526.7 link	c.16G>A	p.Ala6Thr	missense_variant	Exon 3 of 33	5	NM_001142966.3	ENSP00000412060.1		Q9C091-1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000393

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000779

AC:

AN:

128340

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67976

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000196

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000612

AC:

AN:

1308030

Hom.:

Cov.:

AF XY:

0.00000469

AC XY:

AN XY:

640088

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000778

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112250

Hom.:

Cov.:

AF XY:

0.0000182

AC XY:

AN XY:

54852

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000393

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

GREB1L-related disorder

Uncertain:1

Apr 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GREB1L c.16G>A variant is predicted to result in the amino acid substitution p.Ala6Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

T;.;T

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;.

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.5

L;L;L

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-2.7

D;D;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.0080

D;D;.

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.71

MVP

0.34

ClinPred

0.92

GERP RS

5.4

Varity_R

0.34

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over