chr2-11580760-G-A

Variant names:

• chr2-11580760-G-A
• rs76718398
• NM_014668.4:c.829G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014668.4(GREB1):​c.829G>A​(p.Gly277Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000953 in 1,614,190 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (6 hom.)
• Consequence: GREB1 NM_014668.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.08
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071833134).
• BP6: Variant 2-11580760-G-A is Benign according to our data. Variant chr2-11580760-G-A is described in ClinVar as Benign. ClinVar VariationId is 733620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00504 (767/152330) while in subpopulation AFR AF = 0.0178 (738/41570). AF 95% confidence interval is 0.0167. There are 7 homozygotes in GnomAd4. There are 361 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.829G>A	p.Gly277Ser	missense	Exon 7 of 33	NP_055483.2
	GREB1	NM_033090.3		c.829G>A	p.Gly277Ser	missense	Exon 7 of 11	NP_149081.1	Q4ZG55-2
	GREB1	NM_148903.3		c.829G>A	p.Gly277Ser	missense	Exon 7 of 10	NP_683701.2	Q4ZG55-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREB1	ENST00000381486.7	TSL:5 MANE Select	c.829G>A	p.Gly277Ser	missense	Exon 7 of 33	ENSP00000370896.2	Q4ZG55-1
	GREB1	ENST00000234142.9	TSL:1	c.829G>A	p.Gly277Ser	missense	Exon 6 of 32	ENSP00000234142.5	Q4ZG55-1
	GREB1	ENST00000381483.6	TSL:1	c.829G>A	p.Gly277Ser	missense	Exon 7 of 11	ENSP00000370892.2	Q4ZG55-2

Frequencies

GnomAD3 genomes AF: 0.00504 AC: 767 AN: 152212 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00126 AC: 318 AN: 251426 AF XY: 0.000898

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000527 AC: 771 AN: 1461860 Hom.: 6 Cov.: 31 AF XY: 0.000468 AC XY: 340 AN XY: 727234

African (AFR) AF: 0.0190 AC: 635 AN: 33476

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112002

Other (OTH) AF: 0.00139 AC: 84 AN: 60396

GnomAD4 genome AF: 0.00504 AC: 767 AN: 152330 Hom.: 7 Cov.: 33 AF XY: 0.00485 AC XY: 361 AN XY: 74486

African (AFR) AF: 0.0178 AC: 738 AN: 41570

American (AMR) AF: 0.00124 AC: 19 AN: 15308

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00221 Hom.: 9

Bravo AF: 0.00548

ESP6500AA AF: 0.0188 AC: 83

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00173 AC: 210

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.1
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.13
Sift	Benign	0.086	T
Sift4G	Benign	0.081	T
Polyphen		1.0	D
Vest4		0.55
MVP		0.69
MPC		1.2
ClinPred		0.022	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.42
Mutation Taster		=98/2	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: rs76718398; hg19: chr2-11720886;