X-130067236-C-T

Position:

• chrX-130067236-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001421.4(ELF4):​c.1477G>A​(p.Ala493Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,881 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ELF4 NM_001421.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.149

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041483283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELF4	NM_001421.4	c.1477G>A	p.Ala493Thr	missense_variant	9/9	ENST00000308167.10	NP_001412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELF4	ENST00000308167.10	c.1477G>A	p.Ala493Thr	missense_variant	9/9	1	NM_001421.4	ENSP00000311280.6
ELF4	ENST00000335997.11	c.1477G>A	p.Ala493Thr	missense_variant	9/9	1		ENSP00000338608.7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097881 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363339

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.1477G>A (p.A493T) alteration is located in exon 9 (coding exon 8) of the ELF4 gene. This alteration results from a G to A substitution at nucleotide position 1477, causing the alanine (A) at amino acid position 493 to be replaced by a threonine (T). 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	Benign	0.067
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.075	T;T;T
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.62	.;T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.041	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.31	N;N;.
REVEL	Benign	0.032
Sift	Benign	0.20	T;T;.
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.056
MutPred		0.16		Gain of glycosylation at A493 (P = 0.0011);Gain of glycosylation at A493 (P = 0.0011);.;
MVP		0.12
MPC		0.29
ClinPred		0.062	T
GERP RS		0.62
Varity_R		0.061
gMVP		0.21

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: rs1344051914; hg19: chrX-129201211;