Genetic Variant PMF1:p.Gln75Arg (chr1-156232382-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_007221.4(PMF1):c.224A>G(p.Gln75Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,613,436 control chromosomes in the GnomAD database, including 124,676 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.46 ( 17211 hom., cov: 32)

Exomes 𝑓: 0.38 ( 107465 hom. )

Consequence

PMF1
NM_007221.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.83

Publications

71 publications found

Variant links:

Genes affected

PMF1 (HGNC:9112): (polyamine modulated factor 1) Enables leucine zipper domain binding activity and transcription coactivator activity. Involved in chromosome segregation. Located in Golgi apparatus; kinetochore; and nucleoplasm. Part of MIS12/MIND type complex. Implicated in bladder carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

PMF1 links:

PMF1-BGLAP (HGNC:42953): (PMF1-BGLAP readthrough) This locus represents naturally occurring read-through transcription between the neighboring PMF1 (polyamine-modulated factor 1) and BGLAP (bone gamma-carboxyglutamate Gla protein) genes on chromosome 1. Alternative splicing results in multiple transcript variants encoding isoforms that share sequence identity with the upstream gene product, but they contain distinct C-termini due to frameshifts versus the downstream gene coding sequence. [provided by RefSeq, Dec 2010]

PMF1-BGLAP links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=3.4356494E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMF1	NM_007221.4 link	c.224A>G	p.Gln75Arg	missense_variant	Exon 2 of 5	ENST00000368277.3	NP_009152.2	Q6P1K2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMF1	ENST00000368277.3 link	c.224A>G	p.Gln75Arg	missense_variant	Exon 2 of 5	1	NM_007221.4	ENSP00000357260.3		Q6P1K2-1
PMF1-BGLAP	ENST00000490491.5 link	c.224A>G	p.Gln75Arg	missense_variant	Exon 2 of 7	2		ENSP00000475561.1		U3KQ54

Frequencies

GnomAD3 genomes

AF:

0.455

AC:

69094

AN:

151948

Hom.:

17157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.672

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.393

Gnomad ASJ

AF:

0.314

Gnomad EAS

AF:

0.338

Gnomad SAS

AF:

0.329

Gnomad FIN

AF:

0.359

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.379

Gnomad OTH

AF:

0.441

GnomAD2 exomes

AF:

0.377

AC:

94632

AN:

251312

AF XY:

0.369

show subpopulations

Gnomad AFR exome

AF:

0.687

Gnomad AMR exome

AF:

0.343

Gnomad ASJ exome

AF:

0.312

Gnomad EAS exome

AF:

0.334

Gnomad FIN exome

AF:

0.352

Gnomad NFE exome

AF:

0.373

Gnomad OTH exome

AF:

0.367

GnomAD4 exome

AF:

0.379

AC:

554254

AN:

1461370

Hom.:

107465

Cov.:

AF XY:

0.376

AC XY:

273283

AN XY:

727034

show subpopulations

African (AFR)

AF:

0.691

AC:

23122

AN:

33444

American (AMR)

AF:

0.349

AC:

15599

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.314

AC:

8194

AN:

26124

East Asian (EAS)

AF:

0.352

AC:

13966

AN:

39674

South Asian (SAS)

AF:

0.332

AC:

28642

AN:

86236

European-Finnish (FIN)

AF:

0.350

AC:

18698

AN:

53390

Middle Eastern (MID)

AF:

0.360

AC:

2075

AN:

5768

European-Non Finnish (NFE)

AF:

0.378

AC:

420390

AN:

1111670

Other (OTH)

AF:

0.390

AC:

23568

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

18109

36218

54328

72437

90546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13384

26768

40152

53536

66920

<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:

0.455

AC:

69200

AN:

152066

Hom.:

17211

Cov.:

AF XY:

0.449

AC XY:

33405

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.673

AC:

27928

AN:

41484

American (AMR)

AF:

0.393

AC:

5998

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.314

AC:

1088

AN:

3464

East Asian (EAS)

AF:

0.339

AC:

1752

AN:

5162

South Asian (SAS)

AF:

0.328

AC:

1581

AN:

4824

European-Finnish (FIN)

AF:

0.359

AC:

3794

AN:

10574

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.379

AC:

25733

AN:

67960

Other (OTH)

AF:

0.437

AC:

923

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1795

3590

5386

7181

8976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

614

1228

1842

2456

3070

<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:

0.392

Hom.:

41368

Bravo

AF:

0.466

TwinsUK

AF:

0.393

AC:

1458

ALSPAC

AF:

0.380

AC:

1465

ESP6500AA

AF:

0.674

AC:

2971

ESP6500EA

AF:

0.364

AC:

3134

ExAC

AF:

0.385

AC:

46753

EpiCase

AF:

0.361

EpiControl

AF:

0.369

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.035

.;.;.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.13

T;T;T;T;T

MetaRNN

Benign

0.0000034

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.3

.;.;.;N;N

PhyloP100

2.8

PrimateAI

Benign

0.29

PROVEAN

Benign

0.25

.;N;N;N;N

REVEL

Benign

0.064

Sift

Benign

1.0

.;T;T;T;T

Sift4G

Benign

0.97

T;T;T;T;T

Polyphen

0.0

.;.;.;.;B

Vest4

0.028

MPC

0.047

ClinPred

0.00029

GERP RS

4.7

Varity_R

0.065

gMVP

0.042

Mutation Taster

=93/7

polymorphism (auto)

(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