rs1265163

Positions:

• chr6-31166310-C-G
• chr6-31166310-C-T

Variant summary

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

The ENST00000471529.6(POU5F1):​c.-446G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,497,844 control chromosomes in the GnomAD database, including 13,978 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 0.14 (1697 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12281 hom.)
• Consequence: POU5F1 ENST00000471529.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.198

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 (MetaRNN=0.0043299794).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU5F1	NM_002701.6	c.406-263G>C		intron_variant		ENST00000259915.13
POU5F1	NM_001285986.2	c.-671G>C		5_prime_UTR_variant	1/3
POU5F1	NM_203289.6	c.-368G>C		5_prime_UTR_variant	1/4
POU5F1	NM_001173531.3	c.-106+224G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU5F1	ENST00000259915.13	c.406-263G>C		intron_variant		1	NM_002701.6	P1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21727 AN: 150522 Hom.: 1693 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.0637

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.0534

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.144 AC: 19987 AN: 138420 Hom.: 1773 AF XY: 0.138 AC XY: 10342 AN XY: 75034

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.0509

Gnomad EAS exome AF: 0.297

Gnomad SAS exome AF: 0.0965

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.129 AC: 173950 AN: 1347202 Hom.: 12281 Cov.: 85 AF XY: 0.127 AC XY: 84051 AN XY: 663008

Gnomad4 AFR exome AF: 0.147

Gnomad4 AMR exome AF: 0.213

Gnomad4 ASJ exome AF: 0.0529

Gnomad4 EAS exome AF: 0.305

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.144 AC: 21746 AN: 150642 Hom.: 1697 Cov.: 33 AF XY: 0.147 AC XY: 10801 AN XY: 73520

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.0534

Gnomad4 EAS AF: 0.303

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.132

Alfa AF: 0.0667 Hom.: 99

Bravo AF: 0.149

TwinsUK AF: 0.137 AC: 509

ALSPAC AF: 0.136 AC: 523

ExAC AF: 0.0709 AC: 2484

Asia WGS AF: 0.197 AC: 685 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.7
DANN	Benign	0.44
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.0060
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
ClinPred		0.0014	T
GERP RS		-2.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1265163; hg19: chr6-31134087; COSMIC: COSV52563763; COSMIC: COSV52563763;