2-11578289-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014668.4(GREB1):c.638-8C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,608,768 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0099 (34 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (22 hom.)
• Consequence: GREB1 NM_014668.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0006627
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.933

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-11578289-C-A is Benign according to our data. Variant chr2-11578289-C-A is described in ClinVar as [Benign]. Clinvar id is 791848.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00991 (1509/152242) while in subpopulation AFR AF= 0.0346 (1437/41534). AF 95% confidence interval is 0.0331. There are 34 homozygotes in gnomad4. There are 709 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREB1	NM_014668.4	c.638-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000381486.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREB1	ENST00000381486.7	c.638-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_014668.4	P1

Frequencies

GnomAD3 genomes AF: 0.00987 AC: 1501 AN: 152124 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00253 AC: 633 AN: 250418 Hom.: 13 AF XY: 0.00186 AC XY: 252 AN XY: 135330

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000984

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000999 AC: 1455 AN: 1456526 Hom.: 22 Cov.: 31 AF XY: 0.000871 AC XY: 630 AN XY: 723476

Gnomad4 AFR exome AF: 0.0362

Gnomad4 AMR exome AF: 0.00211

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000697

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00991 AC: 1509 AN: 152242 Hom.: 34 Cov.: 33 AF XY: 0.00952 AC XY: 709 AN XY: 74436

Gnomad4 AFR AF: 0.0346

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00485 Hom.: 9

Bravo AF: 0.0116

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 05, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.49
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00066
dbscSNV1_RF	Benign	0.044
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74441544; hg19: chr2-11718415;