Genetic Variant PHB1:p.Arg43Leu (chr17-49411800-C-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_002634.4(PHB1):c.128G>T(p.Arg43Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00689 in 1,614,048 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R43G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0049 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0071 ( 49 hom. )

Consequence

PHB1
NM_002634.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.99

Publications

9 publications found

Variant links:

Genes affected

PHB1 (HGNC:8912): (prohibitin 1) This gene is evolutionarily conserved, and its product is proposed to play a role in human cellular senescence and tumor suppression. Antiproliferative activity is reported to be localized to the 3' UTR, which is proposed to function as a trans-acting regulatory RNA. Several pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

PHB1 links:

ZNF652-AS1 (HGNC:55582): (ZNF652 antisense RNA 1)

ZNF652-AS1 links:

ENSG00000250186 (HGNC:):

ENSG00000250186 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017648518).

BP6

Variant 17-49411800-C-A is Benign according to our data. Variant chr17-49411800-C-A is described in ClinVar as Benign. ClinVar VariationId is 3770639.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 8 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002634.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHB1	NM_002634.4	MANE Select	c.128G>T	p.Arg43Leu	missense	Exon 3 of 7	NP_002625.1	P35232-1
PHB1	NM_001281496.2		c.128G>T	p.Arg43Leu	missense	Exon 3 of 7	NP_001268425.1	P35232-1
PHB1	NM_001281715.2		c.128G>T	p.Arg43Leu	missense	Exon 4 of 8	NP_001268644.1	P35232-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHB1	ENST00000300408.8	TSL:1 MANE Select	c.128G>T	p.Arg43Leu	missense	Exon 3 of 7	ENSP00000300408.3	P35232-1
PHB1	ENST00000511832.6	TSL:2	c.128G>T	p.Arg43Leu	missense	Exon 3 of 7	ENSP00000425035.2	P35232-1
PHB1	ENST00000507748.1	TSL:1	n.435G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00495

AC:

753

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00802

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00813

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00496

AC:

1246

AN:

251280

AF XY:

0.00516

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00874

Gnomad NFE exome

AF:

0.00824

Gnomad OTH exome

AF:

0.00457

GnomAD4 exome

AF:

0.00709

AC:

10365

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00697

AC XY:

5067

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

33478

American (AMR)

AF:

0.00197

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00955

AC:

510

AN:

53412

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00838

AC:

9322

AN:

1111928

Other (OTH)

AF:

0.00648

AC:

391

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

508

1016

1523

2031

2539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.00494

AC:

753

AN:

152282

Hom.:

Cov.:

AF XY:

0.00496

AC XY:

369

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00168

AC:

AN:

41560

American (AMR)

AF:

0.00203

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00802

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00813

AC:

553

AN:

68016

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00468

Hom.:

Bravo

AF:

0.00427

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00884

AC:

ExAC

AF:

0.00511

AC:

620

EpiCase

AF:

0.00753

EpiControl

AF:

0.00694

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Benign

0.031

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.018

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.7

PhyloP100

5.0

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.84

Sift

Benign

0.18

Sift4G

Benign

0.62

Polyphen

0.028

Vest4

0.85

MVP

0.97

MPC

1.4

ClinPred

0.024

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.76

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over