rs1058405

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007348.4(ATF6):c.199A>G(p.Met67Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 1,606,008 control chromosomes in the GnomAD database, including 61,518 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M67L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.21 ( 4127 hom., cov: 32)

Exomes 𝑓: 0.27 ( 57391 hom. )

Consequence

ATF6
NM_007348.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.56

Publications

35 publications found

Variant links:

Genes affected

ATF6 (HGNC:791): (activating transcription factor 6) This gene encodes a transcription factor that activates target genes for the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Although it is a transcription factor, this protein is unusual in that it is synthesized as a transmembrane protein that is embedded in the ER. It functions as an ER stress sensor/transducer, and following ER stress-induced proteolysis, it functions as a nuclear transcription factor via a cis-acting ER stress response element (ERSE) that is present in the promoters of genes encoding ER chaperones. This protein has been identified as a survival factor for quiescent but not proliferative squamous carcinoma cells. There have been conflicting reports about the association of polymorphisms in this gene with diabetes in different populations, but another polymorphism has been associated with increased plasma cholesterol levels. This gene is also thought to be a potential therapeutic target for cystic fibrosis. [provided by RefSeq, Aug 2011]

ATF6 Gene-Disease associations (from GenCC):

achromatopsia 7
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
ATF6-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
achromatopsia
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ATF6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014133751).

BP6

Variant 1-161781951-A-G is Benign according to our data. Variant chr1-161781951-A-G is described in ClinVar as Benign. ClinVar VariationId is 801568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATF6	NM_007348.4 link	c.199A>G	p.Met67Val	missense_variant	Exon 3 of 16	ENST00000367942.4	NP_031374.2	P18850A8K383

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATF6	ENST00000367942.4 link	c.199A>G	p.Met67Val	missense_variant	Exon 3 of 16	1	NM_007348.4	ENSP00000356919.3		P18850

Frequencies

GnomAD3 genomes

AF:

0.209

AC:

31710

AN:

152082

Hom.:

4129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0516

Gnomad AMI

AF:

0.371

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.277

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.304

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.286

Gnomad OTH

AF:

0.218

GnomAD2 exomes

AF:

0.234

AC:

58115

AN:

248664

AF XY:

0.237

show subpopulations

Gnomad AFR exome

AF:

0.0421

Gnomad AMR exome

AF:

0.156

Gnomad ASJ exome

AF:

0.215

Gnomad EAS exome

AF:

0.282

Gnomad FIN exome

AF:

0.291

Gnomad NFE exome

AF:

0.284

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.274

AC:

397833

AN:

1453808

Hom.:

57391

Cov.:

AF XY:

0.271

AC XY:

196369

AN XY:

723558

show subpopulations

African (AFR)

AF:

0.0415

AC:

1385

AN:

33394

American (AMR)

AF:

0.162

AC:

7106

AN:

43980

Ashkenazi Jewish (ASJ)

AF:

0.219

AC:

5700

AN:

26048

East Asian (EAS)

AF:

0.307

AC:

12093

AN:

39438

South Asian (SAS)

AF:

0.168

AC:

14379

AN:

85548

European-Finnish (FIN)

AF:

0.294

AC:

15645

AN:

53284

Middle Eastern (MID)

AF:

0.254

AC:

1456

AN:

5742

European-Non Finnish (NFE)

AF:

0.293

AC:

324543

AN:

1106294

Other (OTH)

AF:

0.258

AC:

15526

AN:

60080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

12433

24866

37300

49733

62166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10550

21100

31650

42200

52750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.208

AC:

31703

AN:

152200

Hom.:

4127

Cov.:

AF XY:

0.208

AC XY:

15512

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0514

AC:

2138

AN:

41564

American (AMR)

AF:

0.199

AC:

3037

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

757

AN:

3468

East Asian (EAS)

AF:

0.277

AC:

1433

AN:

5168

South Asian (SAS)

AF:

0.165

AC:

796

AN:

4824

European-Finnish (FIN)

AF:

0.304

AC:

3213

AN:

10576

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.286

AC:

19462

AN:

67998

Other (OTH)

AF:

0.216

AC:

455

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1250

2500

3749

4999

6249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

332

664

996

1328

1660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.259

Hom.:

15807

Bravo

AF:

0.196

TwinsUK

AF:

0.297

AC:

1102

ALSPAC

AF:

0.290

AC:

1119

ESP6500AA

AF:

0.0567

AC:

250

ESP6500EA

AF:

0.291

AC:

2505

ExAC

AF:

0.234

AC:

28470

Asia WGS

AF:

0.201

AC:

698

AN:

3476

EpiCase

AF:

0.292

EpiControl

AF:

0.282

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Achromatopsia 7

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.15

Eigen

Benign

-0.12

Eigen_PC

Benign

0.024

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

2.6

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.0

REVEL

Benign

0.13

Sift

Benign

0.37

Sift4G

Benign

0.23

Polyphen

0.049

Vest4

0.22

MPC

0.15

ClinPred

0.016

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.076

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over