chr22-39521492-T-C

Variant names:

• chr22-39521492-T-C
• rs1930940865
• NM_182810.3:c.47T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182810.3(ATF4):​c.47T>C​(p.Leu16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATF4 NM_182810.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1362401).

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.47T>C	p.Leu16Ser	missense	Exon 2 of 3	NP_877962.1	P18848
	ATF4	NM_001675.4		c.47T>C	p.Leu16Ser	missense	Exon 1 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.47T>C	p.Leu16Ser	missense	Exon 2 of 3	ENSP00000501863.1	P18848
	ATF4	ENST00000337304.2	TSL:1	c.47T>C	p.Leu16Ser	missense	Exon 1 of 2	ENSP00000336790.2	P18848
	ATF4	ENST00000396680.3	TSL:1	c.47T>C	p.Leu16Ser	missense	Exon 2 of 3	ENSP00000379912.1	P18848

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.041
Sift	Benign	0.030	D
Sift4G	Benign	0.19	T
Polyphen		0.017	B
Vest4		0.13
MutPred		0.37		Gain of disorder (P = 0.0026)
MVP		0.50
MPC		0.0036
ClinPred		0.31	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.095
gMVP		0.16
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs1930940865; hg19: chr22-39917497;