chrX-130066903-G-A

Position:

chrX-130066903-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001421.4(ELF4):c.1810C>T(p.Arg604Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,210,628 control chromosomes in the GnomAD database, including 13 homozygotes. There are 1,550 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., 75 hem., cov: 24)

Exomes 𝑓: 0.0041 ( 12 hom. 1475 hem. )

Consequence

ELF4
NM_001421.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.245

Variant links:

Genes affected

ELF4 (HGNC:3319): (E74 like ETS transcription factor 4) The protein encoded by this gene is a transcriptional activator that binds and activates the promoters of the CSF2, IL3, IL8, and PRF1 genes. The encoded protein is involved in natural killer cell development and function, innate immunity, and induction of cell cycle arrest in naive CD8+ cells. Two transcript variants encoding the same protein have been found for this gene.[provided by RefSeq, Jan 2010]

ELF4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005319476).

BP6

Variant X-130066903-G-A is Benign according to our data. Variant chrX-130066903-G-A is described in ClinVar as [Benign]. Clinvar id is 784732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-130066903-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 75 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELF4	NM_001421.4 link	c.1810C>T	p.Arg604Cys	missense_variant	9/9	ENST00000308167.10	NP_001412.1	Q99607

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELF4	ENST00000308167.10 link	c.1810C>T	p.Arg604Cys	missense_variant	9/9	1	NM_001421.4	ENSP00000311280.6		Q99607
ELF4	ENST00000335997.11 link	c.1810C>T	p.Arg604Cys	missense_variant	9/9	1		ENSP00000338608.7		Q99607

Frequencies

GnomAD3 genomes

AF:

0.00237

AC:

266

AN:

112337

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

AN XY:

34483

show subpopulations

Gnomad AFR

AF:

0.000518

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00122

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.000731

Gnomad FIN

AF:

0.00241

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00408

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.00262

AC:

479

AN:

182865

Hom.:

AF XY:

0.00249

AC XY:

168

AN XY:

67521

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.000948

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00253

Gnomad SAS exome

AF:

0.000629

Gnomad FIN exome

AF:

0.00256

Gnomad NFE exome

AF:

0.00433

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00411

AC:

4509

AN:

1098238

Hom.:

Cov.:

AF XY:

0.00406

AC XY:

1475

AN XY:

363600

show subpopulations

Gnomad4 AFR exome

AF:

0.000682

Gnomad4 AMR exome

AF:

0.000909

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00149

Gnomad4 SAS exome

AF:

0.000905

Gnomad4 FIN exome

AF:

0.00207

Gnomad4 NFE exome

AF:

0.00492

Gnomad4 OTH exome

AF:

0.00289

GnomAD4 genome

AF:

0.00237

AC:

266

AN:

112390

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

AN XY:

34546

show subpopulations

Gnomad4 AFR

AF:

0.000517

Gnomad4 AMR

AF:

0.00122

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.000733

Gnomad4 FIN

AF:

0.00241

Gnomad4 NFE

AF:

0.00408

Gnomad4 OTH

AF:

0.00130

Alfa

AF:

0.00321

Hom.:

118

Bravo

AF:

0.00209

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00554

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00357

AC:

ExAC

AF:

0.00298

AC:

362

EpiCase

AF:

0.00344

EpiControl

AF:

0.00379

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

ELF4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 16, 2022

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

0.061

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-1.0

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.067

T;T;T

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.81

.;T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.0053

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.050

N;N;.

REVEL

Benign

0.080

Sift

Benign

0.23

T;T;.

Sift4G

Benign

0.14

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.070

MVP

0.13

MPC

0.40

ClinPred

0.027

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.078

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over