Genetic Variant POU5F1:p.Pro25Gln (chr6-31170547-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002701.6(POU5F1):c.74C>A(p.Pro25Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,222 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P25L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

POU5F1
NM_002701.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.21

Publications

0 publications found

Variant links:

Genes affected

POU5F1 (HGNC:9221): (POU class 5 homeobox 1) This gene encodes a transcription factor containing a POU homeodomain that plays a key role in embryonic development and stem cell pluripotency. Aberrant expression of this gene in adult tissues is associated with tumorigenesis. This gene can participate in a translocation with the Ewing's sarcoma gene on chromosome 21, which also leads to tumor formation. Alternative splicing, as well as usage of alternative AUG and non-AUG translation initiation codons, results in multiple isoforms. One of the AUG start codons is polymorphic in human populations. Related pseudogenes have been identified on chromosomes 1, 3, 8, 10, and 12. [provided by RefSeq, Oct 2013]

POU5F1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1470721).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU5F1	NM_002701.6 link	c.74C>A	p.Pro25Gln	missense_variant	Exon 1 of 5	ENST00000259915.13	NP_002692.2	Q01860-1D2IYK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POU5F1	ENST00000259915.13 link	c.74C>A	p.Pro25Gln	missense_variant	Exon 1 of 5	1	NM_002701.6	ENSP00000259915.7	Q01860-1
POU5F1	ENST00000461401.1 link	n.112C>A		non_coding_transcript_exon_variant	Exon 1 of 2	1
POU5F1	ENST00000441888.7 link	c.-183-4500C>A		intron_variant	Intron 1 of 4	1		ENSP00000389359.2	F2Z381

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000580

AC:

AN:

172408

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1418222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32488

American (AMR)

AF:

0.00

AC:

AN:

38130

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25284

East Asian (EAS)

AF:

0.00

AC:

AN:

37446

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090566

Other (OTH)

AF:

0.00

AC:

AN:

58684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

0.054

Eigen_PC

Benign

0.054

FATHMM_MKL

Benign

0.63

M_CAP

Benign

0.049

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.

PhyloP100

1.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.11

Sift

Uncertain

0.0090

D;.

Sift4G

Benign

0.28

T;.

Polyphen

0.77

P;.

Vest4

0.35

MutPred

0.11

Gain of solvent accessibility (P = 0.1045);Gain of solvent accessibility (P = 0.1045);

MVP

0.52

MPC

0.63

ClinPred

0.44

GERP RS

2.9

PromoterAI

-0.035

Neutral

(source)

Varity_R

0.041

gMVP

0.16

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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6-31170547-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over