14-77025677-G-A

Variant names:

• chr14-77025677-G-A
• rs781495809
• NM_024496.4:c.2116C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM5 BP4_Strong BS2

The NM_024496.4(IRF2BPL):​c.2116C>T​(p.Pro706Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,562,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P706?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: IRF2BPL NM_024496.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72

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)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-77025676-GG-A is described in ClinVar as [Pathogenic]. Clinvar id is 2284511.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0647189).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF2BPL	NM_024496.4	c.2116C>T	p.Pro706Ser	missense_variant	Exon 1 of 1	ENST00000238647.5	NP_078772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF2BPL	ENST00000238647.5	c.2116C>T	p.Pro706Ser	missense_variant	Exon 1 of 1	6	NM_024496.4	ENSP00000238647.3
LINC02289	ENST00000716908.1	n.304+15377C>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000474 AC: 1 AN: 210868 AF XY: 0.00000894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000106 AC: 15 AN: 1410088 Hom.: 0 Cov.: 31 AF XY: 0.0000158 AC XY: 11 AN XY: 695050

African (AFR) AF: 0.0000311 AC: 1 AN: 32162

American (AMR) AF: 0.00 AC: 0 AN: 39624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22454

East Asian (EAS) AF: 0.00 AC: 0 AN: 39226

South Asian (SAS) AF: 0.00 AC: 0 AN: 77886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5500

European-Non Finnish (NFE) AF: 0.0000129 AC: 14 AN: 1083954

Other (OTH) AF: 0.00 AC: 0 AN: 58080

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2116C>T (p.P706S) alteration is located in exon 1 (coding exon 1) of the IRF2BPL gene. This alteration results from a C to T substitution at nucleotide position 2116, causing the proline (P) at amino acid position 706 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.0061	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.0	N
PhyloP100		2.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	1.3	N
REVEL	Benign	0.22
Sift	Benign	0.97	T
Sift4G	Benign	1.0	T
Polyphen		0.022	B
Vest4		0.18
MutPred		0.15		Gain of catalytic residue at M707 (P = 0.059);
MVP		0.068
MPC		0.85
ClinPred		0.20	T
GERP RS		4.6
Varity_R		0.20
gMVP		0.38
Mutation Taster		=62/38	polymorphism

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

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Other links and lift over

dbSNP: rs781495809; hg19: chr14-77492020;