12-96247282-A-G

Position:

• chr12-96247282-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005230.4(ELK3):​c.550A>G​(p.Arg184Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ELK3 NM_005230.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELK3	NM_005230.4	c.550A>G	p.Arg184Gly	missense_variant	3/5	ENST00000228741.8	NP_005221.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELK3	ENST00000228741.8	c.550A>G	p.Arg184Gly	missense_variant	3/5	1	NM_005230.4	ENSP00000228741.3
ELK3	ENST00000552142.5	c.208-12449A>G		intron_variant		5		ENSP00000449430.1
ELK3	ENST00000549985.1	n.151A>G		splice_region_variant, non_coding_transcript_exon_variant	1/4	3		ENSP00000449420.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000806

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 10, 2024

The c.550A>G (p.R184G) alteration is located in exon 3 (coding exon 2) of the ELK3 gene. This alteration results from a A to G substitution at nucleotide position 550, causing the arginine (R) at amino acid position 184 to be replaced by a glycine (G). 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	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.032	D
Polyphen		0.85	P
Vest4		0.90
MutPred		0.50		Gain of catalytic residue at F185 (P = 0.0058);
MVP		0.74
MPC		0.93
ClinPred		0.91	D
GERP RS		3.2
Varity_R		0.49
gMVP		0.75

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: rs1951864190; hg19: chr12-96641060;