rs13274084

Positions:

• chr8-127416506-A-G

Variant summary

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

The NM_001159542.3(POU5F1B):​c.640A>G​(p.Asn214Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,608,496 control chromosomes in the GnomAD database, including 11,982 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.093 (837 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11145 hom.)
• Consequence: POU5F1B NM_001159542.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.505

Genes affected

POU5F1B (HGNC:9223): (POU class 5 homeobox 1B) This intronless gene was thought to be a transcribed pseudogene of POU class 5 homeobox 1, however, it has been reported that this gene can encode a functional protein. The encoded protein is nearly the same length as and highly similar to the POU class 5 homeobox 1 transcription factor, has been shown to be a weak transcriptional activator and may play a role in carcinogenesis and eye development. [provided by RefSeq, Apr 2009]

CASC8 (HGNC:45129): (cancer susceptibility 8)

PCAT1 (HGNC:43022): (prostate cancer associated transcript 1) This gene produces a long non-coding RNA that promotes cell proliferation and is upregulated in prostate, colorectal, and other cancers. This RNA negatively regulates the BRCA2 tumor suppressor protein and positively regulates Myc oncoprotein. It contains binding sites for microRNAs, and may act as a sponge for microRNAs that regulate cell growth pathways. [provided by RefSeq, Dec 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014190674).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU5F1B	NM_001159542.3	c.640A>G	p.Asn214Asp	missense_variant	1/1	ENST00000696633.1	NP_001153014.1
CASC8	NR_117100.1	n.1176+4323T>C		intron_variant, non_coding_transcript_variant
POU5F1B	NM_001395745.1	c.640A>G	p.Asn214Asp	missense_variant	2/2		NP_001382674.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU5F1B	ENST00000696633.1	c.640A>G	p.Asn214Asp	missense_variant	1/1		NM_001159542.3	ENSP00000512769	P1
CASC8	ENST00000502082.5	n.1176+4323T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0927 AC: 14101 AN: 152042 Hom.: 837 Cov.: 32

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0802

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.0622

Gnomad SAS AF: 0.0711

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.108 AC: 25886 AN: 238938 Hom.: 1728 AF XY: 0.109 AC XY: 14068 AN XY: 128606

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.0563

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.0665

Gnomad SAS exome AF: 0.0675

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.119 AC: 173375 AN: 1456336 Hom.: 11145 Cov.: 113 AF XY: 0.118 AC XY: 85376 AN XY: 723812

Gnomad4 AFR exome AF: 0.0199

Gnomad4 AMR exome AF: 0.0594

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.0784

Gnomad4 SAS exome AF: 0.0699

Gnomad4 FIN exome AF: 0.168

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.0927 AC: 14100 AN: 152160 Hom.: 837 Cov.: 32 AF XY: 0.0932 AC XY: 6929 AN XY: 74372

Gnomad4 AFR AF: 0.0212

Gnomad4 AMR AF: 0.0799

Gnomad4 ASJ AF: 0.195

Gnomad4 EAS AF: 0.0624

Gnomad4 SAS AF: 0.0718

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.106

Alfa AF: 0.124 Hom.: 409

Bravo AF: 0.0843

TwinsUK AF: 0.118 AC: 438

ALSPAC AF: 0.120 AC: 462

ExAC AF: 0.106 AC: 12908

Asia WGS AF: 0.0550 AC: 198 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Benign	0.91
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.82	.;T
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	0.99	P;P
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.1	.;N
REVEL	Benign	0.24
Sift	Uncertain	0.014	.;D
Sift4G	Uncertain	0.015	.;D
Polyphen		0.0020	B;B
Vest4		0.024
MPC		0.044
ClinPred		0.017	T
GERP RS		-2.3
Varity_R		0.30
gMVP		0.17

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: rs13274084; hg19: chr8-128428751; COSMIC: COSV66966695; COSMIC: COSV66966695;