chr8-127416578-G-C

Variant names:

• chr8-127416578-G-C
• rs7002225
• NM_001159542.3:c.712G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001159542.3(POU5F1B):​c.712G>C​(p.Glu238Gln) variant causes a missense change. The variant allele was found at a frequency of 0.5 in 1,601,386 control chromosomes in the GnomAD database, including 204,089 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 0.45 (16656 hom., cov: 32)
  • Exomes 𝑓: 0.51 (187433 hom.)
• Consequence: POU5F1B NM_001159542.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08
• Publications: 21 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.2544813E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159542.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU5F1B	NM_001159542.3	MANE Select	c.712G>C	p.Glu238Gln	missense	Exon 1 of 1	NP_001153014.1
	POU5F1B	NM_001395745.1		c.712G>C	p.Glu238Gln	missense	Exon 2 of 2	NP_001382674.1
	CASC8	NR_117100.1		n.1176+4251C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU5F1B	ENST00000696633.1	MANE Select	c.712G>C	p.Glu238Gln	missense	Exon 1 of 1	ENSP00000512769.1
	CASC8	ENST00000501396.6	TSL:1	n.546+4251C>G		intron	N/A
	CASC8	ENST00000502082.5	TSL:1	n.1176+4251C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68701 AN: 151796 Hom.: 16651 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.478

GnomAD2 exomes AF: 0.505 AC: 115145 AN: 228110 AF XY: 0.506

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.635

Gnomad ASJ exome AF: 0.429

Gnomad EAS exome AF: 0.540

Gnomad FIN exome AF: 0.477

Gnomad NFE exome AF: 0.488

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.505 AC: 732668 AN: 1449472 Hom.: 187433 Cov.: 123 AF XY: 0.507 AC XY: 365255 AN XY: 719760

African (AFR) AF: 0.260 AC: 8673 AN: 33352

American (AMR) AF: 0.624 AC: 26671 AN: 42734

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 11273 AN: 25922

East Asian (EAS) AF: 0.601 AC: 23707 AN: 39414

South Asian (SAS) AF: 0.575 AC: 48544 AN: 84364

European-Finnish (FIN) AF: 0.480 AC: 25282 AN: 52688

Middle Eastern (MID) AF: 0.490 AC: 2791 AN: 5698

European-Non Finnish (NFE) AF: 0.503 AC: 555728 AN: 1105330

Other (OTH) AF: 0.500 AC: 29999 AN: 59970

GnomAD4 genome AF: 0.452 AC: 68722 AN: 151914 Hom.: 16656 Cov.: 32 AF XY: 0.459 AC XY: 34037 AN XY: 74228

African (AFR) AF: 0.276 AC: 11415 AN: 41428

American (AMR) AF: 0.576 AC: 8804 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 1520 AN: 3472

East Asian (EAS) AF: 0.581 AC: 2993 AN: 5152

South Asian (SAS) AF: 0.566 AC: 2720 AN: 4808

European-Finnish (FIN) AF: 0.489 AC: 5149 AN: 10534

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.509 AC: 34562 AN: 67934

Other (OTH) AF: 0.482 AC: 1014 AN: 2104

Alfa AF: 0.453 Hom.: 4677

Bravo AF: 0.449

TwinsUK AF: 0.506 AC: 1877

ALSPAC AF: 0.489 AC: 1885

ExAC AF: 0.483 AC: 58326

Asia WGS AF: 0.565 AC: 1963 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	0.074
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.00073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.54
Sift	Benign	0.040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.063
MPC		0.13
ClinPred		0.071	T
GERP RS		0.20
Varity_R		0.51
gMVP		0.43
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7002225; hg19: chr8-128428823; COSMIC: COSV66966648; COSMIC: COSV66966648;