rs9263795

Positions:

• chr6-31164879-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002701.6(POU5F1):​c.817-12A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0749 in 1,605,982 control chromosomes in the GnomAD database, including 5,373 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.053 (275 hom., cov: 34)
  • Exomes 𝑓: 0.077 (5098 hom.)
• Consequence: POU5F1 NM_002701.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001850
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168

Genes affected

POU5F1 (HGNC:9221): (POU class 5 homeobox 1) This gene encodes a transcription factor containing a POU homeodomain that plays a key role in embryonic development and stem cell pluripotency. Aberrant expression of this gene in adult tissues is associated with tumorigenesis. This gene can participate in a translocation with the Ewing's sarcoma gene on chromosome 21, which also leads to tumor formation. Alternative splicing, as well as usage of alternative AUG and non-AUG translation initiation codons, results in multiple isoforms. One of the AUG start codons is polymorphic in human populations. Related pseudogenes have been identified on chromosomes 1, 3, 8, 10, and 12. [provided by RefSeq, Oct 2013]

TCF19 (HGNC:11629): (transcription factor 19) This gene encodes a protein that contains a PHD-type zinc finger domain and likely functions as a transcription factor. The encoded protein plays a role proliferation and apoptosis of pancreatic beta cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU5F1	NM_002701.6	c.817-12A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000259915.13
POU5F1	NM_001173531.3	c.307-12A>G		splice_polypyrimidine_tract_variant, intron_variant
POU5F1	NM_001285986.2	c.229-12A>G		splice_polypyrimidine_tract_variant, intron_variant
POU5F1	NM_203289.6	c.307-12A>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU5F1	ENST00000259915.13	c.817-12A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002701.6	P1

Frequencies

GnomAD3 genomes AF: 0.0526 AC: 7818 AN: 148728 Hom.: 275 Cov.: 34

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.0436

Gnomad ASJ AF: 0.0367

Gnomad EAS AF: 0.000989

Gnomad SAS AF: 0.00877

Gnomad FIN AF: 0.0469

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.0490

GnomAD3 exomes AF: 0.0479 AC: 11491 AN: 239650 Hom.: 420 AF XY: 0.0487 AC XY: 6364 AN XY: 130620

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.0386

Gnomad EAS exome AF: 0.00144

Gnomad SAS exome AF: 0.0111

Gnomad FIN exome AF: 0.0456

Gnomad NFE exome AF: 0.0780

Gnomad OTH exome AF: 0.0534

GnomAD4 exome AF: 0.0771 AC: 112389 AN: 1457136 Hom.: 5098 Cov.: 72 AF XY: 0.0749 AC XY: 54294 AN XY: 724608

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.0267

Gnomad4 ASJ exome AF: 0.0372

Gnomad4 EAS exome AF: 0.000985

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.0470

Gnomad4 NFE exome AF: 0.0916

Gnomad4 OTH exome AF: 0.0708

GnomAD4 genome AF: 0.0525 AC: 7820 AN: 148846 Hom.: 275 Cov.: 34 AF XY: 0.0496 AC XY: 3596 AN XY: 72550

Gnomad4 AFR AF: 0.0225

Gnomad4 AMR AF: 0.0436

Gnomad4 ASJ AF: 0.0367

Gnomad4 EAS AF: 0.000992

Gnomad4 SAS AF: 0.00899

Gnomad4 FIN AF: 0.0469

Gnomad4 NFE AF: 0.0801

Gnomad4 OTH AF: 0.0485

Alfa AF: 0.0659 Hom.: 144

Bravo AF: 0.0494

Asia WGS AF: 0.00895 AC: 32 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.022
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

LitVar

Other links and lift over

dbSNP: rs9263795; hg19: chr6-31132656;