14-77027274-G-C

Position:

• chr14-77027274-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024496.4(IRF2BPL):​c.519C>G​(p.Tyr173Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRF2BPL NM_024496.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 0.145

Genes affected

IRF2BPL (HGNC:14282): (interferon regulatory factor 2 binding protein like) This gene encodes a transcription factor that may play a role in regulating female reproductive function. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 35 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-77027274-G-C is Pathogenic according to our data. Variant chr14-77027274-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 488960.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr14-77027274-G-C is described in Lovd as [Likely_pathogenic]. Variant chr14-77027274-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF2BPL	NM_024496.4	c.519C>G	p.Tyr173Ter	stop_gained	1/1	ENST00000238647.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF2BPL	ENST00000238647.5	c.519C>G	p.Tyr173Ter	stop_gained	1/1		NM_024496.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2017	The Y173X variant in the IRF2BPL gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function through protein truncation. The Y173X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret Y173X as a variant of uncertain significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -

IRF2BPL-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Oct 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.30	N
MutationTaster	Benign	1.0	D
Vest4		0.16
GERP RS		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555377415; hg19: chr14-77493617;