chr2-11556694-G-T

Variant names:

• chr2-11556694-G-T
• rs532741308
• NM_014668.4:c.80G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014668.4(GREB1):​c.80G>T​(p.Arg27Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R27Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: GREB1 NM_014668.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.48
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

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.80G>T	p.Arg27Leu	missense	Exon 2 of 33	NP_055483.2
	GREB1	NM_033090.3		c.80G>T	p.Arg27Leu	missense	Exon 2 of 11	NP_149081.1	Q4ZG55-2
	GREB1	NM_148903.3		c.80G>T	p.Arg27Leu	missense	Exon 2 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.80G>T	p.Arg27Leu	missense	Exon 2 of 33	ENSP00000370896.2	Q4ZG55-1
	GREB1	ENST00000234142.9	TSL:1	c.80G>T	p.Arg27Leu	missense	Exon 1 of 32	ENSP00000234142.5	Q4ZG55-1
	GREB1	ENST00000381483.6	TSL:1	c.80G>T	p.Arg27Leu	missense	Exon 2 of 11	ENSP00000370892.2	Q4ZG55-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251170 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461662 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111818

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.59		Loss of disorder (P = 0.0582)
MVP		0.73
MPC		1.3
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		0.025	Neutral
Varity_R		0.76
gMVP		0.65
Mutation Taster		=21/79	disease causing

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: rs532741308; hg19: chr2-11696820;