Genetic Variant NM_002701.6:c.*75G>A (chr6-31164526-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002701.6(POU5F1):c.*75G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,561,420 control chromosomes in the GnomAD database, including 74 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 0.0014 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 72 hom. )

Consequence

POU5F1
NM_002701.6 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.297

Publications

2 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:

TCF19 (HGNC:11629): (transcription factor 19) This gene encodes a protein that contains a PHD-type zinc finger domain and likely functions as a transcription factor. The encoded protein plays a role proliferation and apoptosis of pancreatic beta cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

TCF19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00175 (2472/1409108) while in subpopulation EAS AF = 0.047 (1752/37282). AF 95% confidence interval is 0.0452. There are 72 homozygotes in GnomAdExome4. There are 1203 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 215 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
POU5F1	NM_002701.6 link	c.*75G>A	3_prime_UTR_variant	Exon 5 of 5	ENST00000259915.13	NP_002692.2	Q01860-1D2IYK3
POU5F1	NM_001173531.3 link	c.*75G>A	3_prime_UTR_variant	Exon 5 of 5		NP_001167002.1	M1S623
POU5F1	NM_203289.6 link	c.*75G>A	3_prime_UTR_variant	Exon 4 of 4		NP_976034.4	M1S623
POU5F1	NM_001285986.2 link	c.*75G>A	3_prime_UTR_variant	Exon 3 of 3		NP_001272915.1	F2Z381

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU5F1	ENST00000259915.13 link	c.*75G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_002701.6	ENSP00000259915.7		Q01860-1

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

213

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.0131

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00382

GnomAD4 exome

AF:

0.00175

AC:

2472

AN:

1409108

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

1203

AN XY:

696492

show subpopulations

African (AFR)

AF:

0.00280

AC:

AN:

32182

American (AMR)

AF:

0.00121

AC:

AN:

37176

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

25228

East Asian (EAS)

AF:

0.0470

AC:

1752

AN:

37282

South Asian (SAS)

AF:

0.000237

AC:

AN:

80136

European-Finnish (FIN)

AF:

0.0000597

AC:

AN:

50292

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

4316

European-Non Finnish (NFE)

AF:

0.000434

AC:

470

AN:

1084054

Other (OTH)

AF:

0.00101

AC:

AN:

58442

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

152

304

457

609

761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00141

AC:

215

AN:

152312

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41564

American (AMR)

AF:

0.000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.0131

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68034

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00100

Hom.:

Bravo

AF:

0.00157

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

9.0

(source)

DANN

Benign

0.63

PhyloP100

0.30

Mutation Taster

=99/1

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over