Genetic Variant NM_001142966.3:c.277G>A (chr18-21384325-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001142966.3(GREB1L):c.277G>A(p.Glu93Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,551,744 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 17 hom. )

Consequence

GREB1L
NM_001142966.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 9.14

Publications

13 publications found

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 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)

GREB1L links:

GREB1L-AS1 (HGNC:58310):

GREB1L-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039663613).

BP6

Variant 18-21384325-G-A is Benign according to our data. Variant chr18-21384325-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 917910.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00308 (469/152320) while in subpopulation NFE AF = 0.00501 (341/68030). AF 95% confidence interval is 0.00457. There are 2 homozygotes in GnomAd4. There are 215 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GREB1L	NM_001142966.3	MANE Select	c.277G>A	p.Glu93Lys	missense	Exon 4 of 33	NP_001136438.1	Q9C091-1
GREB1L	NM_001410867.1		c.277G>A	p.Glu93Lys	missense	Exon 4 of 34	NP_001397796.1	J3QQW0
GREB1L	NM_001410868.1		c.277G>A	p.Glu93Lys	missense	Exon 4 of 32	NP_001397797.1	Q9C091-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GREB1L	ENST00000424526.7	TSL:5 MANE Select	c.277G>A	p.Glu93Lys	missense	Exon 4 of 33	ENSP00000412060.1	Q9C091-1
GREB1L	ENST00000578368.5	TSL:1	n.382G>A		non_coding_transcript_exon	Exon 3 of 15
GREB1L	ENST00000584446.5	TSL:1	n.548G>A		non_coding_transcript_exon	Exon 4 of 15

Frequencies

GnomAD3 genomes

AF:

0.00308

AC:

469

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00501

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00260

AC:

410

AN:

157698

AF XY:

0.00264

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00239

Gnomad ASJ exome

AF:

0.00270

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00112

Gnomad NFE exome

AF:

0.00460

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00427

AC:

5976

AN:

1399424

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

2856

AN XY:

690226

show subpopulations

African (AFR)

AF:

0.000855

AC:

AN:

31596

American (AMR)

AF:

0.00235

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00294

AC:

AN:

25180

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35728

South Asian (SAS)

AF:

0.000189

AC:

AN:

79230

European-Finnish (FIN)

AF:

0.00140

AC:

AN:

49398

Middle Eastern (MID)

AF:

0.00368

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00506

AC:

5460

AN:

1078818

Other (OTH)

AF:

0.00387

AC:

225

AN:

58072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

283

566

848

1131

1414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

204

408

612

816

1020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00308

AC:

469

AN:

152320

Hom.:

Cov.:

AF XY:

0.00289

AC XY:

215

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000938

AC:

AN:

41584

American (AMR)

AF:

0.00334

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00501

AC:

341

AN:

68030

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00432

Hom.:

Bravo

AF:

0.00300

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00534

AC:

ExAC

AF:

0.00206

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

GREB1L-related disorder (1)

Mayer-Rokitansky-Kuster-Hauser syndrome;C4540497:Renal hypodysplasia/aplasia 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

Eigen

Uncertain

0.58

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.0058

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

9.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.2

REVEL

Benign

0.20

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0080

Polyphen

0.87

Vest4

0.28

MVP

0.20

ClinPred

0.024

GERP RS

5.3

Varity_R

0.31

gMVP

0.43

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over