NM_014668.4:c.638-8C>T

Variant names:

• chr2-11578289-C-T
• rs74441544
• NM_014668.4:c.638-8C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014668.4(GREB1):​c.638-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GREB1 NM_014668.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009428
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.933
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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.638-8C>T		splice_region intron	N/A	NP_055483.2
	GREB1	NM_033090.3		c.638-8C>T		splice_region intron	N/A	NP_149081.1	Q4ZG55-2
	GREB1	NM_148903.3		c.638-8C>T		splice_region intron	N/A	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.638-8C>T		splice_region intron	N/A	ENSP00000370896.2	Q4ZG55-1
	GREB1	ENST00000234142.9	TSL:1	c.638-8C>T		splice_region intron	N/A	ENSP00000234142.5	Q4ZG55-1
	GREB1	ENST00000381483.6	TSL:1	c.638-8C>T		splice_region intron	N/A	ENSP00000370892.2	Q4ZG55-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456528 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723476

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.00 AC: 0 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107844

Other (OTH) AF: 0.00 AC: 0 AN: 60182

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.39
DANN	Benign	0.62
PhyloP100		-0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000094
dbscSNV1_RF	Benign	0.0020
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: rs74441544; hg19: chr2-11718415;