Variant 12-96247105-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005230.4(ELK3):c.373G>C(p.Gly125Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ELK3
NM_005230.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.955

Variant links:

Genes affected

ELK3 (HGNC:3325): (ETS transcription factor ELK3) This gene encodes a member of the ETS-domain transcription factor family and the ternary complex factor (TCF) subfamily. Proteins in this subfamily regulate transcription when recruited by serum response factor to bind to serum response elements. This protein is activated by signal-induced phosphorylation; studies in rodents suggest that it is a transcriptional inhibitor in the absence of Ras, but activates transcription when Ras is present. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ELK3 links:

ELK3 (HGNC:):

ELK3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08253741).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELK3	NM_005230.4 linkuse as main transcript	c.373G>C	p.Gly125Arg	missense_variant	3/5	ENST00000228741.8	NP_005221.2	P41970A0A024RBE2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ELK3	ENST00000228741.8 linkuse as main transcript	c.373G>C	p.Gly125Arg	missense_variant	3/5	1	NM_005230.4	ENSP00000228741.3	P41970
ELK3	ENST00000547860.1 linkuse as main transcript	c.373G>C	p.Gly125Arg	missense_variant	5/5	3		ENSP00000447857.1	F8VUJ0
ELK3	ENST00000552142.5 linkuse as main transcript	c.208-12626G>C		intron_variant		5		ENSP00000449430.1	G3V1Z7
ELK3	ENST00000549985.1 linkuse as main transcript	n.-27G>C		upstream_gene_variant		3		ENSP00000449420.1	H0YIH6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000564

AC:

AN:

248164

Hom.:

AF XY:

0.0000372

AC XY:

AN XY:

134366

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000379

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:

0.000165

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461122

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726880

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000381

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

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:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

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

Aug 07, 2024

The c.373G>C (p.G125R) alteration is located in exon 3 (coding exon 2) of the ELK3 gene. This alteration results from a G to C substitution at nucleotide position 373, causing the glycine (G) at amino acid position 125 to be replaced by an arginine (R). 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

0.19

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.3

DANN

Benign

0.84

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.96

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.85

T;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.083

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;.

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.5

D;N

REVEL

Benign

0.076

Sift

Benign

0.55

T;D

Sift4G

Benign

0.55

T;T

Polyphen

0.0

B;.

Vest4

0.25

MutPred

0.36

Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);

MVP

0.61

MPC

0.30

ClinPred

0.023

GERP RS

-2.0

Varity_R

0.12

gMVP

0.61

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