chrX-85308188-C-T

Variant names:

• chrX-85308188-C-T
• rs75398746
• NM_024921.4:c.986G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001307940.2(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_001307940.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6 B:1
• Conservation: PhyloP100: 3.21
• Publications: 21 publications found

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

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001307940.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POF1B	NM_024921.4	MANE Select	c.986G>A	p.Arg329Gln	missense	Exon 10 of 17	NP_079197.3
	POF1B	NM_001307940.2		c.986G>A	p.Arg329Gln	missense	Exon 10 of 16	NP_001294869.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POF1B	ENST00000262753.9	TSL:1 MANE Select	c.986G>A	p.Arg329Gln	missense	Exon 10 of 17	ENSP00000262753.4
	POF1B	ENST00000373145.3	TSL:1	c.986G>A	p.Arg329Gln	missense	Exon 10 of 16	ENSP00000362238.3
	POF1B	ENST00000871676.1		c.1022G>A	p.Arg341Gln	missense	Exon 11 of 18	ENSP00000541735.1

Frequencies

GnomAD3 genomes AF: 0.00350 AC: 390 AN: 111400 Hom.: 1 Cov.: 23

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

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

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: 0 AN: 29362

South Asian (SAS) AF: 0.0000207 AC: 1 AN: 48403

European-Finnish (FIN) AF: 0.00129 AC: 51 AN: 39612

Middle Eastern (MID) AF: 0.0137 AC: 55 AN: 4010

European-Non Finnish (NFE) AF: 0.00188 AC: 1549 AN: 823110

Other (OTH) AF: 0.00416 AC: 186 AN: 44697

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

African (AFR) AF: 0.00475 AC: 146 AN: 30762

American (AMR) AF: 0.00682 AC: 71 AN: 10407

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 38 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3520

South Asian (SAS) AF: 0.000371 AC: 1 AN: 2694

European-Finnish (FIN) AF: 0.00118 AC: 7 AN: 5939

Middle Eastern (MID) AF: 0.0230 AC: 5 AN: 217

European-Non Finnish (NFE) AF: 0.00202 AC: 107 AN: 53048

Other (OTH) AF: 0.00979 AC: 15 AN: 1532

Alfa AF: 0.00292 Hom.: 137

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	5	-	Premature ovarian failure 2B (7)
-	-	1	not provided (1)
-	1	-	Premature ovarian insufficiency (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.096
Sift	Benign	0.050	D
Sift4G	Uncertain	0.021	D
Polyphen		0.39	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
Mutation Taster		=95/5	disease causing (ClinVar)

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

Other links and lift over

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