rs749067376

Variant names:

• chr2-11562526-G-A
• rs749067376
• NM_014668.4:c.221G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-11562526-G-A
• chr2-11562526-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014668.4(GREB1):​c.221G>A​(p.Gly74Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,452,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GREB1 NM_014668.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.04
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15028432).

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.221G>A	p.Gly74Asp	missense	Exon 3 of 33	NP_055483.2
	GREB1	NM_033090.3		c.221G>A	p.Gly74Asp	missense	Exon 3 of 11	NP_149081.1	Q4ZG55-2
	GREB1	NM_148903.3		c.221G>A	p.Gly74Asp	missense	Exon 3 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.221G>A	p.Gly74Asp	missense	Exon 3 of 33	ENSP00000370896.2	Q4ZG55-1
	GREB1	ENST00000234142.9	TSL:1	c.221G>A	p.Gly74Asp	missense	Exon 2 of 32	ENSP00000234142.5	Q4ZG55-1
	GREB1	ENST00000381483.6	TSL:1	c.221G>A	p.Gly74Asp	missense	Exon 3 of 11	ENSP00000370892.2	Q4ZG55-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000291 AC: 7 AN: 240324 AF XY: 0.0000461

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1452930 Hom.: 0 Cov.: 30 AF XY: 0.0000194 AC XY: 14 AN XY: 722808

African (AFR) AF: 0.00 AC: 0 AN: 32532

American (AMR) AF: 0.00 AC: 0 AN: 43504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25682

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38902

South Asian (SAS) AF: 0.000187 AC: 16 AN: 85478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107994

Other (OTH) AF: 0.00 AC: 0 AN: 59938

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

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	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.024
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.12
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.029	D
Polyphen		0.023	B
Vest4		0.15
MutPred		0.11		Loss of glycosylation at P76 (P = 0.0901)
MVP		0.38
MPC		0.61
ClinPred		0.27	T
GERP RS		5.4
Varity_R		0.19
gMVP		0.21
Mutation Taster		=82/18	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: rs749067376; hg19: chr2-11702652;