rs73175262

Variant names:

• chr2-11618305-G-A
• rs73175262
• NM_014668.4:c.3430G>A

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.56
• Publications: 12 publications found

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]

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014668.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREB1	NM_014668.4	MANE Select	c.3430G>A	p.Glu1144Lys	missense	Exon 22 of 33	NP_055483.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREB1	ENST00000381486.7	TSL:5 MANE Select	c.3430G>A	p.Glu1144Lys	missense	Exon 22 of 33	ENSP00000370896.2	Q4ZG55-1
	GREB1	ENST00000234142.9	TSL:1	c.3430G>A	p.Glu1144Lys	missense	Exon 21 of 32	ENSP00000234142.5	Q4ZG55-1
	GREB1	ENST00000396123.2	TSL:1	c.424G>A	p.Glu142Lys	missense	Exon 5 of 16	ENSP00000379429.1	Q4ZG55-4

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

GnomAD2 exomes AF: 0.00243 AC: 526 AN: 216112 AF XY: 0.00194

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

African (AFR) AF: 0.0350 AC: 1119 AN: 31950

American (AMR) AF: 0.00146 AC: 56 AN: 38254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23158

East Asian (EAS) AF: 0.000766 AC: 30 AN: 39148

South Asian (SAS) AF: 0.0000491 AC: 4 AN: 81520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50768

Middle Eastern (MID) AF: 0.000544 AC: 3 AN: 5512

European-Non Finnish (NFE) AF: 0.0000450 AC: 49 AN: 1088918

Other (OTH) AF: 0.00206 AC: 120 AN: 58134

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

African (AFR) AF: 0.0327 AC: 1350 AN: 41320

American (AMR) AF: 0.00307 AC: 47 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000969 AC: 5 AN: 5162

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 67996

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00373 Hom.: 9

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 v4.9

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
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.15
Sift	Benign	0.70	T
Sift4G	Benign	0.85	T
Polyphen		0.97	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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs73175262; hg19: chr2-11758431;