rs73175262

Positions:

• chr2-11618305-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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. 13/20 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.56

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GREB1	NM_014668.4	c.3430G>A	p.Glu1144Lys	missense_variant	22/33	ENST00000381486.7	NP_055483.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GREB1	ENST00000381486.7	c.3430G>A	p.Glu1144Lys	missense_variant	22/33	5	NM_014668.4	ENSP00000370896.2
GREB1	ENST00000234142.9	c.3430G>A	p.Glu1144Lys	missense_variant	21/32	1		ENSP00000234142.5
GREB1	ENST00000396123.2	c.424G>A	p.Glu142Lys	missense_variant	5/16	1		ENSP00000379429.1
GREB1	ENST00000472040.1	n.*5G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00937 AC: 1423 AN: 151874 Hom.: 26 Cov.: 33

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

GnomAD3 exomes AF: 0.00243 AC: 526 AN: 216112 Hom.: 12 AF XY: 0.00194 AC XY: 230 AN XY: 118364

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 SAS exome AF: 0.0000390

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.: 24 Cov.: 34 AF XY: 0.000841 AC XY: 589 AN XY: 700380

Gnomad4 AFR exome AF: 0.0350

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000766

Gnomad4 SAS exome AF: 0.0000491

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00206

GnomAD4 genome AF: 0.00936 AC: 1422 AN: 151990 Hom.: 26 Cov.: 33 AF XY: 0.00866 AC XY: 643 AN XY: 74292

Gnomad4 AFR AF: 0.0327

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000969

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00300 Hom.: 5

Bravo AF: 0.0114

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0307 AC: 128

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00302 AC: 362

Asia WGS AF: 0.00144 AC: 6 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	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0055	T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.81	.;T;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Benign	0.45	T
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	T
GERP RS		4.0
Varity_R		0.099
gMVP		0.41

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: rs73175262; hg19: chr2-11758431;