dbSNP rs73175262: GREB1:p.Glu1144Lys (chr2-11618305-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_014668.4(GREB1):c.3430G>A(p.Glu1144Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,569,352 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0094 ( 26 hom., cov: 33)

Exomes 𝑓: 0.00097 ( 24 hom. )

Consequence

GREB1
NM_014668.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.56

Publications

12 publications found

Variant links:

Genes affected

GREB1 (HGNC:24885): (growth regulating estrogen receptor binding 1) This gene is an estrogen-responsive gene that is an early response gene in the estrogen receptor-regulated pathway. It is thought to play an important role in hormone-responsive tissues and cancer. Three alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GREB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003469944).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00936 (1422/151990) while in subpopulation AFR AF = 0.0327 (1350/41320). AF 95% confidence interval is 0.0312. There are 26 homozygotes in GnomAd4. There are 643 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREB1	NM_014668.4 link	c.3430G>A	p.Glu1144Lys	missense_variant	Exon 22 of 33	ENST00000381486.7	NP_055483.2	Q4ZG55-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GREB1	ENST00000381486.7 link	c.3430G>A	p.Glu1144Lys	missense_variant	Exon 22 of 33	5	NM_014668.4	ENSP00000370896.2	Q4ZG55-1
GREB1	ENST00000234142.9 link	c.3430G>A	p.Glu1144Lys	missense_variant	Exon 21 of 32	1		ENSP00000234142.5	Q4ZG55-1
GREB1	ENST00000396123.2 link	c.424G>A	p.Glu142Lys	missense_variant	Exon 5 of 16	1		ENSP00000379429.1	Q4ZG55-4
GREB1	ENST00000472040.1 link	n.*5G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00937

AC:

1423

AN:

151874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0328

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000966

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00243

AC:

526

AN:

216112

AF XY:

0.00194

show subpopulations

Gnomad AFR exome

AF:

0.0338

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000769

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000500

Gnomad OTH exome

AF:

0.000400

GnomAD4 exome

AF:

0.000974

AC:

1381

AN:

1417362

Hom.:

Cov.:

AF XY:

0.000841

AC XY:

589

AN XY:

700380

show subpopulations

African (AFR)

AF:

0.0350

AC:

1119

AN:

31950

American (AMR)

AF:

0.00146

AC:

AN:

38254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23158

East Asian (EAS)

AF:

0.000766

AC:

AN:

39148

South Asian (SAS)

AF:

0.0000491

AC:

AN:

81520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50768

Middle Eastern (MID)

AF:

0.000544

AC:

AN:

5512

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

1088918

Other (OTH)

AF:

0.00206

AC:

120

AN:

58134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

162

242

323

404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00936

AC:

1422

AN:

151990

Hom.:

Cov.:

AF XY:

0.00866

AC XY:

643

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.0327

AC:

1350

AN:

41320

American (AMR)

AF:

0.00307

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000969

AC:

AN:

5162

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

67996

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00373

Hom.:

Bravo

AF:

0.0114

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0307

AC:

128

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00302

AC:

362

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0055

T;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.81

.;T;T

MetaRNN

Benign

0.0035

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;.

PhyloP100

3.6

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.97

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.70

T;T;T

Sift4G

Benign

0.85

T;T;T

Polyphen

0.97

D;D;.

Vest4

0.41

MVP

0.35

MPC

0.25

ClinPred

0.024

GERP RS

4.0

Varity_R

0.099

gMVP

0.41

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over