Genetic Variant CASC8:n.546+3812C>G (chr8-127417017-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001395745.1(POU5F1B):c.*71G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 1,552,980 control chromosomes in the GnomAD database, including 459,899 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.73 ( 41718 hom., cov: 28)

Exomes 𝑓: 0.77 ( 418181 hom. )

Consequence

POU5F1B
NM_001395745.1 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.358

Variant links:

Genes affected

CASC8 (HGNC:45129): (cancer susceptibility 8)

CASC8 links:

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]

POU5F1B links:

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]

PCAT1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
POU5F1B	NM_001395745.1 link	c.*71G>C	3_prime_UTR_variant	Exon 2 of 2		NP_001382674.1
CASC8	NR_117100.1 link	n.1176+3812C>G	intron_variant	Intron 5 of 5
POU5F1B	NM_001159542.3 link	c.*71G>C	downstream_gene_variant		ENST00000696633.1	NP_001153014.1	Q06416

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU5F1B	ENST00000696633.1 link	c.*71G>C		downstream_gene_variant			NM_001159542.3	ENSP00000512769.1		Q06416

Frequencies

GnomAD3 genomes

AF:

0.735

AC:

111382

AN:

151580

Hom.:

41708

Cov.:

show subpopulations

Gnomad AFR

AF:

0.584

Gnomad AMI

AF:

0.800

Gnomad AMR

AF:

0.793

Gnomad ASJ

AF:

0.810

Gnomad EAS

AF:

0.842

Gnomad SAS

AF:

0.738

Gnomad FIN

AF:

0.853

Gnomad MID

AF:

0.841

Gnomad NFE

AF:

0.780

Gnomad OTH

AF:

0.771

GnomAD4 exome

AF:

0.771

AC:

1080840

AN:

1401280

Hom.:

418181

Cov.:

AF XY:

0.772

AC XY:

533683

AN XY:

691438

show subpopulations

Gnomad4 AFR exome

AF:

0.572

Gnomad4 AMR exome

AF:

0.787

Gnomad4 ASJ exome

AF:

0.803

Gnomad4 EAS exome

AF:

0.834

Gnomad4 SAS exome

AF:

0.758

Gnomad4 FIN exome

AF:

0.843

Gnomad4 NFE exome

AF:

0.771

Gnomad4 OTH exome

AF:

0.776

GnomAD4 genome

AF:

0.735

AC:

111437

AN:

151700

Hom.:

41718

Cov.:

AF XY:

0.742

AC XY:

55018

AN XY:

74122

show subpopulations

Gnomad4 AFR

AF:

0.583

Gnomad4 AMR

AF:

0.793

Gnomad4 ASJ

AF:

0.810

Gnomad4 EAS

AF:

0.842

Gnomad4 SAS

AF:

0.738

Gnomad4 FIN

AF:

0.853

Gnomad4 NFE

AF:

0.780

Gnomad4 OTH

AF:

0.771

Alfa

AF:

0.749

Hom.:

5102

Bravo

AF:

0.725

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.6

DANN

Benign

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over