X-85278752-A-G

Variant names:

• chrX-85278752-A-G
• rs41300878
• NM_024921.4:c.*669T>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.*669T>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 0.132 in 110,273 control chromosomes in the GnomAD database, including 726 homozygotes. There are 4,027 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (725 hom., 4020 hem., cov: 22)
  • Exomes 𝑓: 0.33 (1 hom. 7 hem.)
• Consequence: POF1B NM_024921.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.923
• 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=-0.83).
• BP6: Variant X-85278752-A-G is Benign according to our data. Variant chrX-85278752-A-G is described in ClinVar as [Benign]. Clinvar id is 368771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POF1B	NM_024921.4	c.*669T>C		3_prime_UTR_variant	Exon 17 of 17	ENST00000262753.9	NP_079197.3
POF1B	XM_005262203.5	c.*669T>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.*669T>C		3_prime_UTR_variant	Exon 17 of 17	1	NM_024921.4	ENSP00000262753.4

Frequencies

GnomAD3 genomes AF: 0.132 AC: 14495 AN: 110187 Hom.: 724 Cov.: 22

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0382

Gnomad AMR AF: 0.0904

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.0932

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.114

GnomAD4 exome AF: 0.333 AC: 13 AN: 39 Hom.: 1 Cov.: 0 AF XY: 0.538 AC XY: 7 AN XY: 13

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.333 AC: 12 AN: 36

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 1 AN: 1

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.132 AC: 14515 AN: 110234 Hom.: 725 Cov.: 22 AF XY: 0.123 AC XY: 4020 AN XY: 32802

African (AFR) AF: 0.131 AC: 3991 AN: 30544

American (AMR) AF: 0.0907 AC: 937 AN: 10335

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 466 AN: 2620

East Asian (EAS) AF: 0.125 AC: 432 AN: 3468

South Asian (SAS) AF: 0.172 AC: 453 AN: 2640

European-Finnish (FIN) AF: 0.153 AC: 901 AN: 5906

Middle Eastern (MID) AF: 0.102 AC: 22 AN: 215

European-Non Finnish (NFE) AF: 0.136 AC: 7114 AN: 52319

Other (OTH) AF: 0.115 AC: 173 AN: 1507

Alfa AF: 0.138 Hom.: 772

Bravo AF: 0.124

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	-0.83
CADD	Benign	5.3
DANN	Benign	0.51
PhyloP100		0.92
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: rs41300878; hg19: chrX-84533758;