8-127416393-G-C

Position:

• chr8-127416393-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001159542.3(POU5F1B):​c.527G>C​(p.Gly176Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G176E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POU5F1B NM_001159542.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.21

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU5F1B	NM_001159542.3	c.527G>C	p.Gly176Ala	missense_variant	1/1	ENST00000696633.1	NP_001153014.1
CASC8	NR_117100.1	n.1176+4436C>G		intron_variant, non_coding_transcript_variant
POU5F1B	NM_001395745.1	c.527G>C	p.Gly176Ala	missense_variant	2/2		NP_001382674.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU5F1B	ENST00000696633.1	c.527G>C	p.Gly176Ala	missense_variant	1/1		NM_001159542.3	ENSP00000512769	P1
CASC8	ENST00000502082.5	n.1176+4436C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1454934 Hom.: 0 Cov.: 104 AF XY: 0.00 AC XY: 0 AN XY: 723020

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;D
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Benign	0.0091	T
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.7	.;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0080	.;D
Polyphen		0.99	D;D
Vest4		0.30
MutPred		0.76		Gain of catalytic residue at G176 (P = 0.0422);Gain of catalytic residue at G176 (P = 0.0422);
MVP		0.73
MPC		0.28
ClinPred		0.99	D
GERP RS		1.1
Varity_R		0.92
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6998061; hg19: chr8-128428638;