chr14-77027274-G-C

Variant names:

• chr14-77027274-G-C
• rs1555377415
• NM_024496.4:c.519C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024496.4(IRF2BPL):​c.519C>G​(p.Tyr173*) 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
• Publications: 0 publications found

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]

LINC02289 (HGNC:53205): (long intergenic non-protein coding RNA 2289)

LOC107984638 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 58 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 VariationId is 488960.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024496.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF2BPL	NM_024496.4	MANE Select	c.519C>G	p.Tyr173*	stop_gained	Exon 1 of 1	NP_078772.1	Q9H1B7
	LOC107984638	NR_190000.1		n.-194G>C		upstream_gene	N/A
	LOC107984638	NR_190001.1		n.-194G>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF2BPL	ENST00000238647.5	TSL:6 MANE Select	c.519C>G	p.Tyr173*	stop_gained	Exon 1 of 1	ENSP00000238647.3	Q9H1B7
	LINC02289	ENST00000716908.1		n.304+13780C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
1	-	-	IRF2BPL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.14
Vest4		0.16
GERP RS		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs1555377415; hg19: chr14-77493617;