rs75398746

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-85308188-C-A
• chrX-85308188-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_024921.4(POF1B):​c.986G>T​(p.Arg329Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000075 in 1,067,209 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R329Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000075 (0 hom. 3 hem.)
• Consequence: POF1B NM_024921.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.21
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POF1B	NM_024921.4	c.986G>T	p.Arg329Leu	missense_variant	Exon 10 of 17	ENST00000262753.9	NP_079197.3
POF1B	NM_001307940.2	c.986G>T	p.Arg329Leu	missense_variant	Exon 10 of 16		NP_001294869.1
POF1B	XM_005262203.5	c.941G>T	p.Arg314Leu	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	c.986G>T	p.Arg329Leu	missense_variant	Exon 10 of 17	1	NM_024921.4	ENSP00000262753.4
POF1B	ENST00000373145.3	c.986G>T	p.Arg329Leu	missense_variant	Exon 10 of 16	1		ENSP00000362238.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000750 AC: 8 AN: 1067209 Hom.: 0 Cov.: 25 AF XY: 0.00000884 AC XY: 3 AN XY: 339501

African (AFR) AF: 0.00 AC: 0 AN: 25669

American (AMR) AF: 0.00 AC: 0 AN: 33616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18712

East Asian (EAS) AF: 0.00 AC: 0 AN: 29362

South Asian (SAS) AF: 0.00 AC: 0 AN: 48401

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39611

Middle Eastern (MID) AF: 0.000748 AC: 3 AN: 4010

European-Non Finnish (NFE) AF: 0.00000243 AC: 2 AN: 823131

Other (OTH) AF: 0.0000671 AC: 3 AN: 44697

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.0	M;M
PhyloP100		3.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.90	P;P
Vest4		0.72
MutPred		0.69		Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);
MVP		0.25
MPC		0.56
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.55
gMVP		0.62
Mutation Taster		=86/14	polymorphism

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: COSV106368177;