8-127416456-T-A

Position:

• chr8-127416456-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001159542.3(POU5F1B):​c.590T>A​(p.Met197Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,456,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POU5F1B NM_001159542.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.76

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU5F1B	NM_001159542.3	c.590T>A	p.Met197Lys	missense_variant	1/1	ENST00000696633.1	NP_001153014.1
POU5F1B	NM_001395745.1	c.590T>A	p.Met197Lys	missense_variant	2/2		NP_001382674.1
CASC8	NR_117100.1	n.1176+4373A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU5F1B	ENST00000696633.1	c.590T>A	p.Met197Lys	missense_variant	1/1		NM_001159542.3	ENSP00000512769.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456812 Hom.: 0 Cov.: 112 AF XY: 0.00000138 AC XY: 1 AN XY: 724060

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2024

The c.590T>A (p.M197K) alteration is located in exon 1 (coding exon 1) of the POU5F1B gene. This alteration results from a T to A substitution at nucleotide position 590, causing the methionine (M) at amino acid position 197 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.75	D;D
Eigen	Benign	0.13
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.0088	T
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.9	.;D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.0020	.;D
Polyphen		1.0	D;D
Vest4		0.47
MutPred		0.83		Gain of methylation at M197 (P = 0.0135);Gain of methylation at M197 (P = 0.0135);
MVP		0.53
MPC		0.33
ClinPred		0.99	D
GERP RS		1.1
Varity_R		0.94
gMVP		0.91

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: rs763703745; hg19: chr8-128428701;