chr1-205620327-G-A

Position:

• chr1-205620327-G-A

Variant summary

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

The NM_001973.4(ELK4):​c.719C>T​(p.Thr240Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,614,228 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ELK4 NM_001973.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50

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]

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=0.0050910413).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELK4	NM_001973.4	c.719C>T	p.Thr240Ile	missense_variant	3/5	ENST00000357992.9	NP_001964.2
ELK4	NM_021795.3	c.719C>T	p.Thr240Ile	missense_variant	3/3		NP_068567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELK4	ENST00000357992.9	c.719C>T	p.Thr240Ile	missense_variant	3/5	1	NM_001973.4	ENSP00000350681.4
ELK4	ENST00000289703.8	c.719C>T	p.Thr240Ile	missense_variant	3/3	1		ENSP00000289703.4
ELK4	ENST00000616704.4	n.719C>T		non_coding_transcript_exon_variant	3/10	2		ENSP00000483628.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 251480 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000154 AC: 225 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.000173 AC XY: 126 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00490

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74500

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000337 Hom.: 1

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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

Sep 17, 2021

The c.719C>T (p.T240I) alteration is located in exon 3 (coding exon 2) of the ELK4 gene. This alteration results from a C to T substitution at nucleotide position 719, causing the threonine (T) at amino acid position 240 to be replaced by an isoleucine (I). 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	0.075
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.6
DANN	Benign	0.94
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.027
Sift	Benign	0.066	T;D
Sift4G	Benign	0.20	T;T
Polyphen		0.0	B;B
Vest4		0.028
MVP		0.22
MPC		0.14
ClinPred		0.020	T
GERP RS		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.19

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: rs146453123; hg19: chr1-205589455;