Variant 19-49932496-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001193646.2(ATF5):c.253C>G(p.Pro85Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,457,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P85P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000058 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATF5
NM_001193646.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.103

Variant links:

Genes affected

ATF5 (HGNC:790): (activating transcription factor 5) Enables several functions, including DNA-binding transcription activator activity, RNA polymerase II-specific; RNA polymerase II transcription regulatory region sequence-specific DNA binding activity; and tubulin binding activity. Involved in several processes, including fat cell differentiation; regulation of cell cycle process; and regulation of transcription, DNA-templated. Located in centrosome; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ATF5 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016323745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ATF5	NM_001193646.2 linkuse as main transcript	c.253C>G	p.Pro85Ala	missense_variant	3/3	ENST00000423777.7
ATF5	NM_001290746.2 linkuse as main transcript	c.253C>G	p.Pro85Ala	missense_variant	3/3
ATF5	NM_012068.6 linkuse as main transcript	c.253C>G	p.Pro85Ala	missense_variant	4/4
ATF5	XM_011526629.4 linkuse as main transcript	c.253C>G	p.Pro85Ala	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ATF5	ENST00000423777.7 linkuse as main transcript	c.253C>G	p.Pro85Ala	missense_variant	3/3	1	NM_001193646.2	P1
ATF5	ENST00000595125.5 linkuse as main transcript	c.253C>G	p.Pro85Ala	missense_variant	4/4	2		P1
ATF5	ENST00000596658.1 linkuse as main transcript	c.253C>G	p.Pro85Ala	missense_variant	3/3	2
ATF5	ENST00000597227.5 linkuse as main transcript	c.253C>G	p.Pro85Ala	missense_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150920

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00198

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:

0.00

Gnomad OTH

AF:

0.000484

GnomAD3 exomes

AF:

0.000113

AC:

AN:

246936

Hom.:

AF XY:

0.0000818

AC XY:

AN XY:

134534

show subpopulations

Gnomad AFR exome

AF:

0.00175

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:

0.0000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000576

AC:

AN:

1457648

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

725250

show subpopulations

Gnomad4 AFR exome

AF:

0.00234

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:

0.0000188

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000543

AC:

AN:

151028

Hom.:

Cov.:

AF XY:

0.000651

AC XY:

AN XY:

73732

show subpopulations

Gnomad4 AFR

AF:

0.00197

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:

0.00

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000126

Hom.:

Bravo

AF:

0.000688

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.253C>G (p.P85A) alteration is located in exon 4 (coding exon 2) of the ATF5 gene. This alteration results from a C to G substitution at nucleotide position 253, causing the proline (P) at amino acid position 85 to be replaced by an alanine (A). 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

0.046

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.51

DANN

Benign

0.59

DEOGEN2

Benign

0.016

T;T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.49

.;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.016

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.31

.;N;.;.

REVEL

Benign

0.044

Sift

Benign

0.080

.;T;.;.

Sift4G

Uncertain

0.011

D;D;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.21

MVP

0.25

MPC

0.019

ClinPred

0.018

GERP RS

-3.2

Varity_R

0.021

gMVP

0.26

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over