rs4894

Variant names:

• chr22-39521510-A-C
• rs4894
• NM_182810.3:c.65A>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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 0.30 (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
• Publications: 40 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ATF4	NM_182810.3	c.65A>C	p.Gln22Pro	missense_variant	Exon 2 of 3	ENST00000674920.3	NP_877962.1
ATF4	NM_001675.4	c.65A>C	p.Gln22Pro	missense_variant	Exon 1 of 2		NP_001666.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATF4	ENST00000674920.3	c.65A>C	p.Gln22Pro	missense_variant	Exon 2 of 3		NM_182810.3	ENSP00000501863.1

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

GnomAD2 exomes AF: 0.305 AC: 75476 AN: 247404 AF XY: 0.308

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 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

African (AFR) AF: 0.277 AC: 9159 AN: 33110

American (AMR) AF: 0.289 AC: 12666 AN: 43832

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 9134 AN: 25870

East Asian (EAS) AF: 0.147 AC: 5806 AN: 39442

South Asian (SAS) AF: 0.344 AC: 29430 AN: 85540

European-Finnish (FIN) AF: 0.321 AC: 17128 AN: 53294

Middle Eastern (MID) AF: 0.326 AC: 1384 AN: 4248

European-Non Finnish (NFE) AF: 0.309 AC: 341734 AN: 1105342

Other (OTH) AF: 0.304 AC: 18170 AN: 59800

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

African (AFR) AF: 0.278 AC: 11545 AN: 41488

American (AMR) AF: 0.285 AC: 4353 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1216 AN: 3470

East Asian (EAS) AF: 0.188 AC: 975 AN: 5174

South Asian (SAS) AF: 0.338 AC: 1625 AN: 4808

European-Finnish (FIN) AF: 0.331 AC: 3499 AN: 10562

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21381 AN: 67976

Other (OTH) AF: 0.309 AC: 654 AN: 2116

Alfa AF: 0.313 Hom.: 3243

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
PhyloP100		1.1
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
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4894; hg19: chr22-39917515; COSMIC: COSV57478471; COSMIC: COSV57478471;