2-175074815-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001880.4(ATF2):c.1312T>A(p.Ser438Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000581 in 1,613,474 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: ATF2 NM_001880.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.31

Genes affected

ATF2 (HGNC:784): (activating transcription factor 2) This gene encodes a transcription factor that is a member of the leucine zipper family of DNA binding proteins. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions This protein binds to the cAMP-responsive element (CRE), an octameric palindrome. It forms a homodimer or a heterodimer with c-Jun and stimulates CRE-dependent transcription. This protein is also a histone acetyltransferase (HAT) that specifically acetylates histones H2B and H4 in vitro; thus it may represent a class of sequence-specific factors that activate transcription by direct effects on chromatin components. The encoded protein may also be involved in cell's DNA damage response independent of its role in transcriptional regulation. Several alternatively spliced transcript variants have been found for this gene [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051841915).
• BS2: High AC in GnomAd at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATF2	NM_001880.4	c.1312T>A	p.Ser438Thr	missense_variant	14/14	ENST00000264110.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATF2	ENST00000264110.7	c.1312T>A	p.Ser438Thr	missense_variant	14/14	1	NM_001880.4

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000394 AC: 98 AN: 248926 Hom.: 0 AF XY: 0.000401 AC XY: 54 AN XY: 134688

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000753

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000599 AC: 875 AN: 1461196 Hom.: 1 Cov.: 31 AF XY: 0.000593 AC XY: 431 AN XY: 726908

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000735

Gnomad4 OTH exome AF: 0.000514

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74446

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000554 Hom.: 0

Bravo AF: 0.000348

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The c.1312T>A (p.S438T) alteration is located in exon 14 (coding exon 12) of the ATF2 gene. This alteration results from a T to A substitution at nucleotide position 1312, causing the serine (S) at amino acid position 438 to be replaced by a threonine (T). 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	0.064
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	21
Dann	Benign	0.95
DEOGEN2	Benign	0.17	T;.;.;T;.;T;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.052	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	2.0	M;.;.;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.46	N;N;N;N;N;.;N;N
REVEL	Benign	0.17
Sift	Benign	0.21	T;T;T;T;T;.;T;T
Sift4G	Benign	0.31	T;T;T;T;T;T;T;T
Polyphen		0.23	B;.;.;.;.;.;B;.
Vest4		0.21
MVP		0.75
MPC		0.74
ClinPred		0.088	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.095
gMVP		0.17

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: rs142443599; hg19: chr2-175939543;