rs2394882

chr6-31164872-A-Cchr6-31164872-A-Gchr6-31164872-A-T

Variant summary

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

The NM_002701.6(POU5F1):c.817-5T>G 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 0.667 in 1,609,460 control chromosomes in the GnomAD database, including 360,389 homozygotes. 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: 𝑓 0.69 (36757 hom., cov: 33)
  • Exomes 𝑓: 0.66 (323632 hom.)
• Consequence: POU5F1 NM_002701.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.05026
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.165

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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU5F1	NM_002701.6	c.817-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000259915.13
POU5F1	NM_001173531.3	c.307-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
POU5F1	NM_001285986.2	c.229-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
POU5F1	NM_203289.6	c.307-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU5F1	ENST00000259915.13	c.817-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002701.6	P1

Frequencies

GnomAD3 genomes AF: 0.691 AC: 104940 AN: 151924 Hom.: 36727 Cov.: 33

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.695

GnomAD3 exomes AF: 0.642 AC: 154716 AN: 240940 Hom.: 50121 AF XY: 0.640 AC XY: 83985 AN XY: 131290

Gnomad AFR exome AF: 0.789

Gnomad AMR exome AF: 0.596

Gnomad ASJ exome AF: 0.718

Gnomad EAS exome AF: 0.651

Gnomad SAS exome AF: 0.575

Gnomad FIN exome AF: 0.573

Gnomad NFE exome AF: 0.659

Gnomad OTH exome AF: 0.671

GnomAD4 exome AF: 0.665 AC: 968539 AN: 1457418 Hom.: 323632 Cov.: 85 AF XY: 0.661 AC XY: 479421 AN XY: 724794

Gnomad4 AFR exome AF: 0.796

Gnomad4 AMR exome AF: 0.608

Gnomad4 ASJ exome AF: 0.718

Gnomad4 EAS exome AF: 0.600

Gnomad4 SAS exome AF: 0.583

Gnomad4 FIN exome AF: 0.577

Gnomad4 NFE exome AF: 0.674

Gnomad4 OTH exome AF: 0.675

GnomAD4 genome AF: 0.691 AC: 105019 AN: 152042 Hom.: 36757 Cov.: 33 AF XY: 0.685 AC XY: 50868 AN XY: 74304

Gnomad4 AFR AF: 0.792

Gnomad4 AMR AF: 0.679

Gnomad4 ASJ AF: 0.727

Gnomad4 EAS AF: 0.635

Gnomad4 SAS AF: 0.568

Gnomad4 FIN AF: 0.568

Gnomad4 NFE AF: 0.663

Gnomad4 OTH AF: 0.694

Alfa AF: 0.676 Hom.: 54998

Bravo AF: 0.705

Asia WGS AF: 0.665 AC: 2310 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	5.4
Dann	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.050
dbscSNV1_RF	Benign	0.28
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: rs2394882; hg19: chr6-31132649; COSMIC: COSV52565439; COSMIC: COSV52565439;