NM_024921.4:c.*312A>C

Variant names:

• chrX-85279109-T-G
• rs12008480
• NM_024921.4:c.*312A>C

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.*312A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 198,248 control chromosomes in the GnomAD database, including 3,459 homozygotes. There are 9,475 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (2449 hom., 6565 hem., cov: 22)
  • Exomes 𝑓: 0.16 (1010 hom. 2910 hem.)
• Consequence: POF1B NM_024921.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.308
• Publications: 3 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=-0.94).
• BP6: Variant X-85279109-T-G is Benign according to our data. Variant chrX-85279109-T-G is described in ClinVar as [Benign]. Clinvar id is 368776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POF1B	NM_024921.4	c.*312A>C		3_prime_UTR_variant	Exon 17 of 17	ENST00000262753.9	NP_079197.3
POF1B	XM_005262203.5	c.*312A>C		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.*312A>C		3_prime_UTR_variant	Exon 17 of 17	1	NM_024921.4	ENSP00000262753.4

Frequencies

GnomAD3 genomes AF: 0.215 AC: 23659 AN: 109826 Hom.: 2451 Cov.: 22

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.0399

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.119

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.188

GnomAD4 exome AF: 0.158 AC: 14001 AN: 88379 Hom.: 1010 Cov.: 0 AF XY: 0.163 AC XY: 2910 AN XY: 17879

African (AFR) AF: 0.389 AC: 1323 AN: 3398

American (AMR) AF: 0.150 AC: 466 AN: 3104

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 665 AN: 3501

East Asian (EAS) AF: 0.198 AC: 1688 AN: 8507

South Asian (SAS) AF: 0.199 AC: 184 AN: 925

European-Finnish (FIN) AF: 0.162 AC: 949 AN: 5859

Middle Eastern (MID) AF: 0.126 AC: 50 AN: 396

European-Non Finnish (NFE) AF: 0.136 AC: 7637 AN: 56229

Other (OTH) AF: 0.161 AC: 1039 AN: 6460

GnomAD4 genome AF: 0.216 AC: 23696 AN: 109869 Hom.: 2449 Cov.: 22 AF XY: 0.202 AC XY: 6565 AN XY: 32469

African (AFR) AF: 0.402 AC: 12161 AN: 30260

American (AMR) AF: 0.153 AC: 1573 AN: 10263

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 472 AN: 2612

East Asian (EAS) AF: 0.153 AC: 534 AN: 3488

South Asian (SAS) AF: 0.197 AC: 517 AN: 2630

European-Finnish (FIN) AF: 0.155 AC: 915 AN: 5920

Middle Eastern (MID) AF: 0.131 AC: 28 AN: 214

European-Non Finnish (NFE) AF: 0.137 AC: 7186 AN: 52302

Other (OTH) AF: 0.188 AC: 283 AN: 1503

Alfa AF: 0.155 Hom.: 5626

Bravo AF: 0.219

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	-0.94
CADD	Benign	0.90
DANN	Benign	0.52
PhyloP100		-0.31
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: rs12008480; hg19: chrX-84534115;