Genetic Variant NM_002701.6:c.238G>C (chr6-31170383-C-G) – 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.238G>C(p.Val80Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,366 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. V80I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

POU5F1
NM_002701.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.29

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=0.072601646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU5F1	NM_002701.6 link	c.238G>C	p.Val80Leu	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.238G>C	p.Val80Leu	missense_variant	Exon 1 of 5	1	NM_002701.6	ENSP00000259915.7	Q01860-1
POU5F1	ENST00000461401.1 link	n.276G>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
POU5F1	ENST00000441888.7 link	c.-183-4336G>C		intron_variant	Intron 1 of 4	1		ENSP00000389359.2	F2Z381

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460366

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111826

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.072

T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.30

M_CAP

Benign

0.041

MetaRNN

Benign

0.073

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.89

L;.

PhyloP100

1.3

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.050

N;.

REVEL

Benign

0.043

Sift

Benign

0.30

T;.

Sift4G

Benign

0.82

T;.

Polyphen

0.43

B;.

Vest4

0.11

MutPred

0.28

Loss of catalytic residue at V80 (P = 0.1538);Loss of catalytic residue at V80 (P = 0.1538);

MVP

0.48

MPC

0.55

ClinPred

0.13

GERP RS

2.2

PromoterAI

0.0064

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.061

gMVP

0.17

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over