8-127416170-G-C

Variant names:

• chr8-127416170-G-C
• rs552351247
• NM_001159542.3:c.304G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001159542.3(POU5F1B):​c.304G>C​(p.Gly102Arg) 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. 16/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POU5F1B NM_001159542.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04857251).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU5F1B	NM_001159542.3	c.304G>C	p.Gly102Arg	missense_variant	Exon 1 of 1	ENST00000696633.1	NP_001153014.1
POU5F1B	NM_001395745.1	c.304G>C	p.Gly102Arg	missense_variant	Exon 2 of 2		NP_001382674.1
CASC8	NR_117100.1	n.1176+4659C>G		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU5F1B	ENST00000696633.1	c.304G>C	p.Gly102Arg	missense_variant	Exon 1 of 1		NM_001159542.3	ENSP00000512769.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 113

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.036
DANN	Benign	0.60
DEOGEN2	Benign	0.0049	T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.62	.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.83	L;L
PhyloP100		-1.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.51	.;N
REVEL	Benign	0.16
Sift	Benign	1.0	.;T
Sift4G	Benign	0.48	.;T
Polyphen		0.0020	B;B
Vest4		0.042
MutPred		0.24		Gain of methylation at G102 (P = 0.0211);Gain of methylation at G102 (P = 0.0211);
MVP		0.11
MPC		0.045
ClinPred		0.053	T
GERP RS		-2.1
Varity_R		0.044
gMVP		0.26
Mutation Taster		=97/3	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: rs552351247; hg19: chr8-128428415;