chr14-77025590-T-A

Position:

• chr14-77025590-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024496.4(IRF2BPL):​c.2203A>T​(p.Ser735Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,607,468 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S735I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (5 hom.)
• Consequence: IRF2BPL NM_024496.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 0.407

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03294909).
• BP6: Variant 14-77025590-T-A is Benign according to our data. Variant chr14-77025590-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1284940.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-77025590-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00134 (204/152344) while in subpopulation NFE AF= 0.00219 (149/68032). AF 95% confidence interval is 0.0019. There are 1 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 204 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF2BPL	NM_024496.4	c.2203A>T	p.Ser735Cys	missense_variant	1/1	ENST00000238647.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF2BPL	ENST00000238647.5	c.2203A>T	p.Ser735Cys	missense_variant	1/1		NM_024496.4	P1

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152226 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00109 AC: 267 AN: 244974 Hom.: 0 AF XY: 0.00102 AC XY: 135 AN XY: 132598

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.000241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00234 AC: 3400 AN: 1455124 Hom.: 5 Cov.: 31 AF XY: 0.00230 AC XY: 1662 AN XY: 723708

Gnomad4 AFR exome AF: 0.000393

Gnomad4 AMR exome AF: 0.000277

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.000544

Gnomad4 NFE exome AF: 0.00296

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00134 AC: 204 AN: 152344 Hom.: 1 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74496

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00178 Hom.: 1

Bravo AF: 0.00124

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00122 AC: 148

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	IRF2BPL: BS1 -

IRF2BPL-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.033	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.69	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.27
Sift	Uncertain	0.020	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.54
MVP		0.21
MPC		0.81
ClinPred		0.051	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.32
gMVP		0.48

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: rs141239534; hg19: chr14-77491933;