2-11566599-G-C

Position:

• chr2-11566599-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014668.4(GREB1):​c.397G>C​(p.Val133Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GREB1 NM_014668.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.80

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GREB1	NM_014668.4	c.397G>C	p.Val133Leu	missense_variant	4/33	ENST00000381486.7	NP_055483.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GREB1	ENST00000381486.7	c.397G>C	p.Val133Leu	missense_variant	4/33	5	NM_014668.4	ENSP00000370896.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2024

The c.397G>C (p.V133L) alteration is located in exon 4 (coding exon 3) of the GREB1 gene. This alteration results from a G to C substitution at nucleotide position 397, causing the valine (V) at amino acid position 133 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;.;T;.;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.59	D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.4	M;M;.;M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.3	N;D;D;D;N
REVEL	Benign	0.29
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.60
MutPred		0.27		Loss of methylation at K138 (P = 0.0864);Loss of methylation at K138 (P = 0.0864);.;Loss of methylation at K138 (P = 0.0864);Loss of methylation at K138 (P = 0.0864);
MVP		0.75
MPC		1.1
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.49
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-11706725;