rs4894

Positions:

• chr22-39521510-A-C
• chr22-39521510-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182810.3(ATF4):​c.65A>C​(p.Gln22Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,602,562 control chromosomes in the GnomAD database, including 76,463 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.30 (6968 hom., cov: 32)
  • Exomes 𝑓: 0.31 (69495 hom.)
• Consequence: ATF4 NM_182810.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

Genes affected

ATF4 (HGNC:786): (activating transcription factor 4) This gene encodes a transcription factor that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 (CREB-2). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the AP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins. These transcription factors share a leucine zipper region that is involved in protein-protein interactions, located C-terminal to a stretch of basic amino acids that functions as a DNA binding domain. Two alternative transcripts encoding the same protein have been described. Two pseudogenes are located on the X chromosome at q28 in a region containing a large inverted duplication. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012947917).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATF4	NM_182810.3	c.65A>C	p.Gln22Pro	missense_variant	2/3	ENST00000674920.3	NP_877962.1
ATF4	NM_001675.4	c.65A>C	p.Gln22Pro	missense_variant	1/2		NP_001666.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATF4	ENST00000674920.3	c.65A>C	p.Gln22Pro	missense_variant	2/3		NM_182810.3	ENSP00000501863	P1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45644 AN: 151966 Hom.: 6968 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.309

GnomAD3 exomes AF: 0.305 AC: 75476 AN: 247404 Hom.: 11828 AF XY: 0.308 AC XY: 41255 AN XY: 133820

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.340

Gnomad FIN exome AF: 0.323

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.307 AC: 444611 AN: 1450478 Hom.: 69495 Cov.: 35 AF XY: 0.309 AC XY: 222852 AN XY: 720102

Gnomad4 AFR exome AF: 0.277

Gnomad4 AMR exome AF: 0.289

Gnomad4 ASJ exome AF: 0.353

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.344

Gnomad4 FIN exome AF: 0.321

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.304

GnomAD4 genome AF: 0.300 AC: 45664 AN: 152084 Hom.: 6968 Cov.: 32 AF XY: 0.300 AC XY: 22286 AN XY: 74364

Gnomad4 AFR AF: 0.278

Gnomad4 AMR AF: 0.285

Gnomad4 ASJ AF: 0.350

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.331

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.309

Alfa AF: 0.314 Hom.: 3219

Bravo AF: 0.295

TwinsUK AF: 0.298 AC: 1105

ALSPAC AF: 0.325 AC: 1252

ESP6500AA AF: 0.270 AC: 1190

ESP6500EA AF: 0.319 AC: 2741

ExAC AF: 0.303 AC: 36848

Asia WGS AF: 0.327 AC: 1138 AN: 3478

EpiCase AF: 0.326

EpiControl AF: 0.323

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.37	T;T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.65	.;.;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	0.00025	P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.82	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.058	T;T;T
Sift4G	Benign	0.067	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.11
MPC		0.0038
ClinPred		0.012	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4894; hg19: chr22-39917515; COSMIC: COSV57478471; COSMIC: COSV57478471;