rs75398746

Positions:

• chrX-85308188-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 12/20 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4 B:1
• Conservation: PhyloP100: 3.21

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
POF1B	NM_024921.4	c.986G>A	p.Arg329Gln	missense_variant	10/17	ENST00000262753.9
POF1B	NM_001307940.2	c.986G>A	p.Arg329Gln	missense_variant	10/16
POF1B	XM_005262203.5	c.941G>A	p.Arg314Gln	missense_variant	10/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POF1B	ENST00000262753.9	c.986G>A	p.Arg329Gln	missense_variant	10/17	1	NM_024921.4	A2
POF1B	ENST00000373145.3	c.986G>A	p.Arg329Gln	missense_variant	10/16	1		P4

Frequencies

GnomAD3 genomes AF: 0.00350 AC: 390 AN: 111400 Hom.: 1 Cov.: 23 AF XY: 0.00327 AC XY: 110 AN XY: 33634

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

GnomAD3 exomes AF: 0.00271 AC: 461 AN: 170226 Hom.: 0 AF XY: 0.00223 AC XY: 127 AN XY: 56824

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 SAS 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.: 4 Cov.: 25 AF XY: 0.00216 AC XY: 733 AN XY: 339504

Gnomad4 AFR exome AF: 0.00401

Gnomad4 AMR exome AF: 0.00372

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000207

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00188

Gnomad4 OTH exome AF: 0.00416

GnomAD4 genome AF: 0.00350 AC: 390 AN: 111449 Hom.: 1 Cov.: 23 AF XY: 0.00326 AC XY: 110 AN XY: 33693

Gnomad4 AFR AF: 0.00475

Gnomad4 AMR AF: 0.00682

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000371

Gnomad4 FIN AF: 0.00118

Gnomad4 NFE AF: 0.00202

Gnomad4 OTH AF: 0.00979

Alfa AF: 0.00277 Hom.: 126

Bravo AF: 0.00458

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00678 AC: 26

ESP6500EA AF: 0.00253 AC: 17

ExAC AF: 0.00261 AC: 316

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Premature ovarian failure 2B Pathogenic:3 Uncertain:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -
Likely pathogenic, no assertion criteria provided	research	Reproductive Development, Murdoch Childrens Research Institute	Feb 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 26, 2018	Lacombe et al. (2006) identified the POF1B c.986G>A (p.Arg329Gln) variant in a homozygous state in five sisters with POF from a consanguineous Lebanese family. The variant was also identified in a heterozygous state in the unaffected mother and an unaffected sister. The p.Arg329Gln variant has also been reported in two additional patients with POF, including in a heterozygous state in one patient with a second unidentified variant and in one patient with the p.Arg329Gln variant on one allele and a balanced translocation on the other (Bione et al. 2004; Ledig et al. 2015). The p.Arg329Gln variant was found in a heterozygous state in a total of seven of 992 controls from the above studies, and is reported at a frequency of 0.007634 in the admixed American population of the 1000 Genomes Project. Lacombe et al. (2006) found that in vitro binding to non-muscle actin filaments was diminished four-fold in the p.Arg329Gln variant protein compared to the wild type, and Padovano et al. (2011) demonstrated that cells expressing the p.Arg329Gln variant have mislocalized and misassembled tight junctions, were dysmorphic with altered monolayer organization, and showed defects in ciliogenesis and cystogenesis. Based on the evidence, the p.Arg329Gln variant is classified as as a variant of unknown significance but suspicious for pathogenicity for premature ovarian failure 2B. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 19, 2020	- -

Premature ovarian insufficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	20
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;.
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.18	A;A
PrimateAI	Benign	0.44	T
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	T
GERP RS		5.0
Varity_R		0.29
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs75398746; hg19: chrX-84563194; COSMIC: COSV99427834;