chr22-39521618-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_182810.3(ATF4):​c.173C>T​(p.Ser58Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ATF4
NM_182810.3 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.12
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.35894707).
BS2
High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATF4NM_182810.3 linkc.173C>T p.Ser58Phe missense_variant Exon 2 of 3 ENST00000674920.3 NP_877962.1 P18848
ATF4NM_001675.4 linkc.173C>T p.Ser58Phe missense_variant Exon 1 of 2 NP_001666.2 P18848

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATF4ENST00000674920.3 linkc.173C>T p.Ser58Phe missense_variant Exon 2 of 3 NM_182810.3 ENSP00000501863.1 P18848

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251242
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135834
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461866
Hom.:
0
Cov.:
33
AF XY:
0.0000248
AC XY:
18
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 29, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.173C>T (p.S58F) alteration is located in exon 1 (coding exon 1) of the ATF4 gene. This alteration results from a C to T substitution at nucleotide position 173, causing the serine (S) at amino acid position 58 to be replaced by a phenylalanine (F). 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
0.10
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.43
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
D;D;D
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.82
.;.;T
M_CAP
Benign
0.067
D
MetaRNN
Benign
0.36
T;T;T
MetaSVM
Benign
-0.52
T
MutationAssessor
Benign
2.0
M;M;M
PrimateAI
Benign
0.42
T
PROVEAN
Uncertain
-2.6
D;D;D
REVEL
Benign
0.15
Sift
Benign
0.047
D;D;D
Sift4G
Uncertain
0.022
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.29
MutPred
0.31
Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);
MVP
0.74
MPC
0.0040
ClinPred
0.82
D
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.19
gMVP
0.22

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs767028222; hg19: chr22-39917623; API