chr22-39521950-C-T

Variant names:

• chr22-39521950-C-T
• rs140428747
• NM_182810.3:c.404C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_182810.3(ATF4):​c.404C>T​(p.Pro135Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,613,286 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0068 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (8 hom.)
• Consequence: ATF4 NM_182810.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.81
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057759285).
• BP6: Variant 22-39521950-C-T is Benign according to our data. Variant chr22-39521950-C-T is described in ClinVar as Benign. ClinVar VariationId is 783889.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00679 (1029/151644) while in subpopulation AFR AF = 0.0239 (987/41318). AF 95% confidence interval is 0.0227. There are 8 homozygotes in GnomAd4. There are 487 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1029 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182810.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF4	NM_182810.3	MANE Select	c.404C>T	p.Pro135Leu	missense	Exon 3 of 3	NP_877962.1	P18848
	ATF4	NM_001675.4		c.404C>T	p.Pro135Leu	missense	Exon 2 of 2	NP_001666.2	P18848

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF4	ENST00000674920.3	MANE Select	c.404C>T	p.Pro135Leu	missense	Exon 3 of 3	ENSP00000501863.1	P18848
	ATF4	ENST00000337304.2	TSL:1	c.404C>T	p.Pro135Leu	missense	Exon 2 of 2	ENSP00000336790.2	P18848
	ATF4	ENST00000396680.3	TSL:1	c.404C>T	p.Pro135Leu	missense	Exon 3 of 3	ENSP00000379912.1	P18848

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 1030 AN: 151524 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00193

GnomAD2 exomes AF: 0.00166 AC: 417 AN: 251164 AF XY: 0.00114

Gnomad AFR exome AF: 0.0230

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000694 AC: 1014 AN: 1461642 Hom.: 8 Cov.: 33 AF XY: 0.000597 AC XY: 434 AN XY: 727120

African (AFR) AF: 0.0259 AC: 866 AN: 33470

American (AMR) AF: 0.00121 AC: 54 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111814

Other (OTH) AF: 0.00124 AC: 75 AN: 60382

GnomAD4 genome AF: 0.00679 AC: 1029 AN: 151644 Hom.: 8 Cov.: 32 AF XY: 0.00658 AC XY: 487 AN XY: 74054

African (AFR) AF: 0.0239 AC: 987 AN: 41318

American (AMR) AF: 0.00230 AC: 35 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67894

Other (OTH) AF: 0.00191 AC: 4 AN: 2096

Alfa AF: 0.000965 Hom.: 0

Bravo AF: 0.00751

ESP6500AA AF: 0.0222 AC: 98

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00181 AC: 220

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.8
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.13
Sift	Benign	0.097	T
Sift4G	Benign	0.099	T
Polyphen		1.0	D
Vest4		0.18
MVP		0.59
MPC		0.011
ClinPred		0.022	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.087
gMVP		0.15
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140428747; hg19: chr22-39917955; COSMIC: COSV104631524; COSMIC: COSV104631524;