chr2-11576392-T-A

Variant names:

• chr2-11576392-T-A
• rs762408918
• NM_014668.4:c.494T>A

Variant summary

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

The NM_014668.4(GREB1):​c.494T>A​(p.Phe165Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: GREB1 NM_014668.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88
• Publications: 1 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, 0.82

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.494T>A	p.Phe165Tyr	missense	Exon 5 of 33	NP_055483.2
	GREB1	NM_033090.3		c.494T>A	p.Phe165Tyr	missense	Exon 5 of 11	NP_149081.1	Q4ZG55-2
	GREB1	NM_148903.3		c.494T>A	p.Phe165Tyr	missense	Exon 5 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.494T>A	p.Phe165Tyr	missense	Exon 5 of 33	ENSP00000370896.2	Q4ZG55-1
	GREB1	ENST00000234142.9	TSL:1	c.494T>A	p.Phe165Tyr	missense	Exon 4 of 32	ENSP00000234142.5	Q4ZG55-1
	GREB1	ENST00000381483.6	TSL:1	c.494T>A	p.Phe165Tyr	missense	Exon 5 of 11	ENSP00000370892.2	Q4ZG55-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251386 AF XY: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.45		Gain of ubiquitination at K162 (P = 0.0741)
MVP		0.78
MPC		1.2
ClinPred		0.94	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.56
gMVP		0.58
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs762408918; hg19: chr2-11716518;