22-39521955-A-T

Position:

• chr22-39521955-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_182810.3(ATF4):​c.409A>T​(p.Thr137Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 1,605,392 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (44 hom.)
• Consequence: ATF4 NM_182810.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.170

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032248497).
• BP6: Variant 22-39521955-A-T is Benign according to our data. Variant chr22-39521955-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 784891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 639 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATF4	NM_182810.3	c.409A>T	p.Thr137Ser	missense_variant	3/3	ENST00000674920.3	NP_877962.1
ATF4	NM_001675.4	c.409A>T	p.Thr137Ser	missense_variant	2/2		NP_001666.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATF4	ENST00000674920.3	c.409A>T	p.Thr137Ser	missense_variant	3/3		NM_182810.3	ENSP00000501863	P1

Frequencies

GnomAD3 genomes AF: 0.00425 AC: 637 AN: 149748 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.00175

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00197

Gnomad FIN AF: 0.000977

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.00696

Gnomad OTH AF: 0.00532

GnomAD3 exomes AF: 0.00481 AC: 1207 AN: 251130 Hom.: 10 AF XY: 0.00476 AC XY: 646 AN XY: 135744

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00555

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00353

Gnomad FIN exome AF: 0.00199

Gnomad NFE exome AF: 0.00694

Gnomad OTH exome AF: 0.00702

GnomAD4 exome AF: 0.00615 AC: 8947 AN: 1455526 Hom.: 44 Cov.: 33 AF XY: 0.00615 AC XY: 4454 AN XY: 724288

Gnomad4 AFR exome AF: 0.00135

Gnomad4 AMR exome AF: 0.00552

Gnomad4 ASJ exome AF: 0.000891

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.00386

Gnomad4 FIN exome AF: 0.00151

Gnomad4 NFE exome AF: 0.00710

Gnomad4 OTH exome AF: 0.00502

GnomAD4 genome AF: 0.00426 AC: 639 AN: 149866 Hom.: 4 Cov.: 32 AF XY: 0.00394 AC XY: 288 AN XY: 73086

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00411

Gnomad4 ASJ AF: 0.00175

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00197

Gnomad4 FIN AF: 0.000977

Gnomad4 NFE AF: 0.00696

Gnomad4 OTH AF: 0.00527

Alfa AF: 0.00619 Hom.: 2

Bravo AF: 0.00454

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00466 AC: 566

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00823

EpiControl AF: 0.00782

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.6
DANN	Benign	0.77
DEOGEN2	Benign	0.31	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.37	.;.;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.30	N;N;N
REVEL	Benign	0.058
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.016	B;B;B
Vest4		0.064
MVP		0.19
MPC		0.0043
ClinPred		0.0047	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.061

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: rs150385569; hg19: chr22-39917960; COSMIC: COSV99046514; COSMIC: COSV99046514;