X-85308188-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_024921.4(POF1B):c.986G>A(p.Arg329Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,178,639 control chromosomes in the GnomAD database, including 5 homozygotes. There are 843 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0035 ( 1 hom., 110 hem., cov: 23)

Exomes 𝑓: 0.0022 ( 4 hom. 733 hem. )

Consequence

POF1B
NM_024921.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6B:1

Conservation

PhyloP100: 3.21

Publications

21 publications found

Variant links:

Genes affected

POF1B (HGNC:13711): (POF1B actin binding protein) Premature ovarian failure (POF) is characterized by primary or secondary amenorrhea in women less than 40 years old. Two POF susceptibility regions called "POF1" and "POF2" have been identified by breakpoint mapping of X-autosome translocations. POF1 extends from Xq21-qter while POF2 extends from Xq13.3 to Xq21.1. This gene, POF1B, resides in the POF2 region. This gene is expressed at trace levels in mouse prenatal ovary and is barely detectable or absent from adult ovary, in human and in the mouse respectively. This gene's expression is restricted to epithelia with its highest expression in the epidermis, and oro-pharyngeal and gastro-intestinal tracts. The protein encoded by this gene binds non-muscle actin filaments. The role this gene may play in the etiology of premature ovarian failure remains to be determined. [provided by RefSeq, Jan 2010]

POF1B Gene-Disease associations (from GenCC):

premature ovarian failure 2B
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

POF1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017275214).

BS2

High Hemizygotes in GnomAd4 at 110 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POF1B	NM_024921.4 link	c.986G>A	p.Arg329Gln	missense_variant	Exon 10 of 17	ENST00000262753.9	NP_079197.3	Q8WVV4-2
POF1B	NM_001307940.2 link	c.986G>A	p.Arg329Gln	missense_variant	Exon 10 of 16		NP_001294869.1	Q8WVV4-1
POF1B	XM_005262203.5 link	c.941G>A	p.Arg314Gln	missense_variant	Exon 10 of 17		XP_005262260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POF1B	ENST00000262753.9 link	c.986G>A	p.Arg329Gln	missense_variant	Exon 10 of 17	1	NM_024921.4	ENSP00000262753.4		Q8WVV4-2
POF1B	ENST00000373145.3 link	c.986G>A	p.Arg329Gln	missense_variant	Exon 10 of 16	1		ENSP00000362238.3		Q8WVV4-1

Frequencies

GnomAD3 genomes

AF:

0.00350

AC:

390

AN:

111400

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00476

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00683

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000370

Gnomad FIN

AF:

0.00118

Gnomad MID

AF:

0.0209

Gnomad NFE

AF:

0.00202

Gnomad OTH

AF:

0.00991

GnomAD2 exomes

AF:

0.00271

AC:

461

AN:

170226

AF XY:

0.00223

show subpopulations

Gnomad AFR exome

AF:

0.00563

Gnomad AMR exome

AF:

0.00362

Gnomad ASJ exome

AF:

0.0135

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000759

Gnomad NFE exome

AF:

0.00216

Gnomad OTH exome

AF:

0.00660

GnomAD4 exome

AF:

0.00217

AC:

2320

AN:

1067190

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

733

AN XY:

339504

show subpopulations

African (AFR)

AF:

0.00401

AC:

103

AN:

25667

American (AMR)

AF:

0.00372

AC:

125

AN:

33617

Ashkenazi Jewish (ASJ)

AF:

0.0134

AC:

250

AN:

18712

East Asian (EAS)

AF:

0.00

AC:

AN:

29362

South Asian (SAS)

AF:

0.0000207

AC:

AN:

48403

European-Finnish (FIN)

AF:

0.00129

AC:

AN:

39612

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

4010

European-Non Finnish (NFE)

AF:

0.00188

AC:

1549

AN:

823110

Other (OTH)

AF:

0.00416

AC:

186

AN:

44697

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

146

220

293

366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00350

AC:

390

AN:

111449

Hom.:

Cov.:

AF XY:

0.00326

AC XY:

110

AN XY:

33693

show subpopulations

African (AFR)

AF:

0.00475

AC:

146

AN:

30762

American (AMR)

AF:

0.00682

AC:

AN:

10407

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3520

South Asian (SAS)

AF:

0.000371

AC:

AN:

2694

European-Finnish (FIN)

AF:

0.00118

AC:

AN:

5939

Middle Eastern (MID)

AF:

0.0230

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00202

AC:

107

AN:

53048

Other (OTH)

AF:

0.00979

AC:

AN:

1532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00292

Hom.:

137

Bravo

AF:

0.00458

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00678

AC:

ESP6500EA

AF:

0.00253

AC:

ExAC

AF:

0.00261

AC:

316

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Premature ovarian failure 2B

Pathogenic:2Uncertain:5

Jul 10, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jul 01, 2006

OMIM

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

- -

Nov 22, 2024

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The POF1B c.986G>A (p.Arg329Gln) missense variant has been identified in individuals with premature ovarian failure and was shown to segregate with disease in one family (PMID:16773570; 15459172; 25676666). The highest frequency of this allele in the Genome Aggregation Database is 0.01419 in the Middle Eastern population, which includes two homozygotes (version 4.1.0). An additional 3 homozygotes are reported in the total population. Functional studies suggest that this variant impacts protein function (PMID: 16773570; 21940798). Multiple lines of computational evidence suggest the variant may not impact the gene or gene product. Based on the evidence the c.986G>A (p.Arg329Gln) variant is classified as a variant of uncertain significance for premature ovarian failure. -

Mar 19, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 09, 2021

Reproductive Development, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:research

- -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. -

Premature ovarian insufficiency

Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

T;.

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

PhyloP100

3.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.096

Sift

Benign

0.050

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.39

B;B

Vest4

0.42

MVP

0.18

MPC

0.21

ClinPred

0.015

GERP RS

5.0

Varity_R

0.29

gMVP

0.43

Mutation Taster

=95/5

disease causing (ClinVar)

(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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X-85308188-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over