8-127416207-C-A

Variant names:

• chr8-127416207-C-A
• rs771322061
• NM_001159542.3:c.341C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001159542.3(POU5F1B):​c.341C>A​(p.Pro114His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P114R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POU5F1B NM_001159542.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.622
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16547221).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU5F1B	NM_001159542.3	MANE Select	c.341C>A	p.Pro114His	missense	Exon 1 of 1	NP_001153014.1	Q06416
	POU5F1B	NM_001395745.1		c.341C>A	p.Pro114His	missense	Exon 2 of 2	NP_001382674.1	Q06416
	CASC8	NR_117100.1		n.1176+4622G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU5F1B	ENST00000696633.1	MANE Select	c.341C>A	p.Pro114His	missense	Exon 1 of 1	ENSP00000512769.1	Q06416
	CASC8	ENST00000501396.6	TSL:1	n.546+4622G>T		intron	N/A
	CASC8	ENST00000502082.5	TSL:1	n.1176+4622G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 113

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.62
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.031
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.073
MutPred		0.19		Loss of glycosylation at P114 (P = 0.053)
MVP		0.31
MPC		0.28
ClinPred		0.88	D
GERP RS		0.39
Varity_R		0.25
gMVP		0.32
Mutation Taster		=98/2	polymorphism

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: rs771322061; hg19: chr8-128428452;