Variant 1-205620406-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001973.4(ELK4):c.640A>G(p.Ile214Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I214T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ELK4
NM_001973.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0440

Variant links:

Genes affected

ELK4 (HGNC:3326): (ETS transcription factor ELK4) This gene is a member of the Ets family of transcription factors and of the ternary complex factor (TCF) subfamily. Proteins of the TCF subfamily form a ternary complex by binding to the the serum response factor and the serum reponse element in the promoter of the c-fos proto-oncogene. The protein encoded by this gene is phosphorylated by the kinases, MAPK1 and MAPK8. Several transcript variants have been described for this gene. [provided by RefSeq, Jul 2008]

ELK4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.026516318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELK4	NM_001973.4 linkuse as main transcript	c.640A>G	p.Ile214Val	missense_variant	3/5	ENST00000357992.9	NP_001964.2	P28324-1A0A024R985Q8IXL1
ELK4	NM_021795.3 linkuse as main transcript	c.640A>G	p.Ile214Val	missense_variant	3/3		NP_068567.1	P28324-2A0A024R997Q8IXL1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ELK4	ENST00000357992.9 linkuse as main transcript	c.640A>G	p.Ile214Val	missense_variant	3/5	1	NM_001973.4	ENSP00000350681.4	P28324-1
ELK4	ENST00000289703.8 linkuse as main transcript	c.640A>G	p.Ile214Val	missense_variant	3/3	1		ENSP00000289703.4	P28324-2
ELK4	ENST00000616704.4 linkuse as main transcript	n.640A>G		non_coding_transcript_exon_variant	3/10	2		ENSP00000483628.1	P28324-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251454

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000105

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2024

The c.640A>G (p.I214V) alteration is located in exon 3 (coding exon 2) of the ELK4 gene. This alteration results from a A to G substitution at nucleotide position 640, causing the isoleucine (I) at amino acid position 214 to be replaced by a valine (V). 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

0.060

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.1

DANN

Benign

0.35

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.55

T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.027

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.41

N;N

PROVEAN

Benign

-0.040

N;N

REVEL

Benign

0.025

Sift

Benign

0.86

T;T

Sift4G

Benign

0.58

T;T

Polyphen

0.0

B;B

Vest4

0.036

MVP

0.31

MPC

0.11

ClinPred

0.011

GERP RS

-2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.013

gMVP

0.13

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