rs2181440

Variant names:

• chrX-130067204-C-T
• rs2181440
• NM_001421.4:c.1509G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001421.4(ELF4):​c.1509G>A​(p.Thr503Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,207,984 control chromosomes in the GnomAD database, including 27,550 homozygotes. There are 100,244 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (2250 hom., 7342 hem., cov: 24)
  • Exomes 𝑓: 0.26 (25300 hom. 92902 hem.)
• Consequence: ELF4 NM_001421.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.45
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• autoinflammatory syndrome, familial, X-linked, Behcet-like 2

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant X-130067204-C-T is Benign according to our data. Variant chrX-130067204-C-T is described in ClinVar as Benign. ClinVar VariationId is 402824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001421.4. 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
	ELF4	NM_001421.4	MANE Select	c.1509G>A	p.Thr503Thr	synonymous	Exon 9 of 9	NP_001412.1
	ELF4	NM_001127197.2		c.1509G>A	p.Thr503Thr	synonymous	Exon 9 of 9	NP_001120669.1
	ELF4	NM_001440765.1		c.1509G>A	p.Thr503Thr	synonymous	Exon 9 of 9	NP_001427694.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELF4	ENST00000308167.10	TSL:1 MANE Select	c.1509G>A	p.Thr503Thr	synonymous	Exon 9 of 9	ENSP00000311280.6
	ELF4	ENST00000335997.11	TSL:1	c.1509G>A	p.Thr503Thr	synonymous	Exon 9 of 9	ENSP00000338608.7
	ELF4	ENST00000880884.1		c.1509G>A	p.Thr503Thr	synonymous	Exon 10 of 10	ENSP00000550943.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 24061 AN: 111875 Hom.: 2251 Cov.: 24

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.245

GnomAD2 exomes AF: 0.254 AC: 45328 AN: 178787 AF XY: 0.249

Gnomad AFR exome AF: 0.0665

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.278

Gnomad EAS exome AF: 0.114

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.274

GnomAD4 exome AF: 0.257 AC: 281919 AN: 1096059 Hom.: 25300 Cov.: 34 AF XY: 0.257 AC XY: 92902 AN XY: 361801

African (AFR) AF: 0.0671 AC: 1768 AN: 26345

American (AMR) AF: 0.362 AC: 12695 AN: 35065

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 5293 AN: 19282

East Asian (EAS) AF: 0.133 AC: 4019 AN: 30180

South Asian (SAS) AF: 0.253 AC: 13639 AN: 53982

European-Finnish (FIN) AF: 0.262 AC: 10577 AN: 40321

Middle Eastern (MID) AF: 0.254 AC: 1046 AN: 4111

European-Non Finnish (NFE) AF: 0.263 AC: 220980 AN: 840786

Other (OTH) AF: 0.259 AC: 11902 AN: 45987

GnomAD4 genome AF: 0.215 AC: 24056 AN: 111925 Hom.: 2250 Cov.: 24 AF XY: 0.215 AC XY: 7342 AN XY: 34129

African (AFR) AF: 0.0708 AC: 2195 AN: 30992

American (AMR) AF: 0.364 AC: 3881 AN: 10659

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 733 AN: 2639

East Asian (EAS) AF: 0.114 AC: 402 AN: 3535

South Asian (SAS) AF: 0.239 AC: 647 AN: 2710

European-Finnish (FIN) AF: 0.254 AC: 1539 AN: 6053

Middle Eastern (MID) AF: 0.315 AC: 68 AN: 216

European-Non Finnish (NFE) AF: 0.265 AC: 14003 AN: 52913

Other (OTH) AF: 0.242 AC: 370 AN: 1531

Alfa AF: 0.257 Hom.: 2428

Bravo AF: 0.216

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.11
DANN	Benign	0.59
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs2181440; hg19: chrX-129201179; COSMIC: COSV57453562;