NM_024921.4:c.*368G>T

Variant names:

• chrX-85279053-C-A
• rs6617041
• NM_024921.4:c.*368G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024921.4(POF1B):​c.*368G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0617 in 144,794 control chromosomes in the GnomAD database, including 629 homozygotes. There are 2,361 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (454 hom., 2071 hem., cov: 22)
  • Exomes 𝑓: 0.050 (175 hom. 290 hem.)
• Consequence: POF1B NM_024921.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.296
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-85279053-C-A is Benign according to our data. Variant chrX-85279053-C-A is described in ClinVar as [Benign]. Clinvar id is 368774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POF1B	NM_024921.4	c.*368G>T		3_prime_UTR_variant	Exon 17 of 17	ENST00000262753.9	NP_079197.3
POF1B	XM_005262203.5	c.*368G>T		3_prime_UTR_variant	Exon 17 of 17		XP_005262260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POF1B	ENST00000262753.9	c.*368G>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_024921.4	ENSP00000262753.4

Frequencies

GnomAD3 genomes AF: 0.0652 AC: 7196 AN: 110378 Hom.: 458 Cov.: 22

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.0557

Gnomad FIN AF: 0.00333

Gnomad MID AF: 0.0297

Gnomad NFE AF: 0.00430

Gnomad OTH AF: 0.0675

GnomAD4 exome AF: 0.0504 AC: 1732 AN: 34369 Hom.: 175 Cov.: 0 AF XY: 0.0498 AC XY: 290 AN XY: 5821

African (AFR) AF: 0.163 AC: 243 AN: 1488

American (AMR) AF: 0.122 AC: 200 AN: 1641

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 19 AN: 1394

East Asian (EAS) AF: 0.368 AC: 971 AN: 2641

South Asian (SAS) AF: 0.0445 AC: 23 AN: 517

European-Finnish (FIN) AF: 0.00452 AC: 6 AN: 1326

Middle Eastern (MID) AF: 0.0278 AC: 4 AN: 144

European-Non Finnish (NFE) AF: 0.00579 AC: 131 AN: 22634

Other (OTH) AF: 0.0522 AC: 135 AN: 2584

GnomAD4 genome AF: 0.0652 AC: 7204 AN: 110425 Hom.: 454 Cov.: 22 AF XY: 0.0628 AC XY: 2071 AN XY: 32957

African (AFR) AF: 0.146 AC: 4445 AN: 30470

American (AMR) AF: 0.101 AC: 1036 AN: 10287

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 62 AN: 2622

East Asian (EAS) AF: 0.334 AC: 1153 AN: 3456

South Asian (SAS) AF: 0.0551 AC: 147 AN: 2668

European-Finnish (FIN) AF: 0.00333 AC: 20 AN: 6007

Middle Eastern (MID) AF: 0.0279 AC: 6 AN: 215

European-Non Finnish (NFE) AF: 0.00430 AC: 226 AN: 52510

Other (OTH) AF: 0.0726 AC: 109 AN: 1501

Alfa AF: 0.0332 Hom.: 2273

Bravo AF: 0.0839

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Premature ovarian failure 2B Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.6
DANN	Benign	0.58
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs6617041; hg19: chrX-84534059;