8-127416741-C-G

Position:

• chr8-127416741-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001159542.3(POU5F1B):​c.875C>G​(p.Ala292Gly) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: POU5F1B NM_001159542.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0910

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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062111437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU5F1B	NM_001159542.3	c.875C>G	p.Ala292Gly	missense_variant	1/1	ENST00000696633.1	NP_001153014.1
POU5F1B	NM_001395745.1	c.875C>G	p.Ala292Gly	missense_variant	2/2		NP_001382674.1
CASC8	NR_117100.1	n.1176+4088G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU5F1B	ENST00000696633.1	c.875C>G	p.Ala292Gly	missense_variant	1/1		NM_001159542.3	ENSP00000512769.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 111

GnomAD4 genome Cov.: 31

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

Apr 28, 2022

The c.875C>G (p.A292G) alteration is located in exon 1 (coding exon 1) of the POU5F1B gene. This alteration results from a C to G substitution at nucleotide position 875, causing the alanine (A) at amino acid position 292 to be replaced by a glycine (G). 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	0.080
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	2.7
DANN	Benign	0.45
DEOGEN2	Benign	0.00051	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0098	N
LIST_S2	Benign	0.47	.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.68	.;N
REVEL	Benign	0.23
Sift	Benign	0.050	.;D
Sift4G	Benign	0.44	.;T
Polyphen		0.031	B;B
Vest4		0.067
MutPred		0.35		Gain of glycosylation at S289 (P = 0.1009);Gain of glycosylation at S289 (P = 0.1009);
MVP		0.099
MPC		0.042
ClinPred		0.054	T
GERP RS		-0.039
Varity_R		0.035
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-128428986;