1-161791522-C-T

Variant names:

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.469C>T(p.Pro157Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0939 in 1,607,720 control chromosomes in the GnomAD database, including 12,636 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1613 hom., cov: 32)

Exomes 𝑓: 0.091 ( 11023 hom. )

Consequence

ATF6
NM_007348.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.453

Publications

27 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=0.002713263).

BP6

Variant 1-161791522-C-T is Benign according to our data. Variant chr1-161791522-C-T is described in ClinVar as Benign. ClinVar VariationId is 1164407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATF6	NM_007348.4 link	c.469C>T	p.Pro157Ser	missense_variant	Exon 5 of 16	ENST00000367942.4	NP_031374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATF6	ENST00000367942.4 link	c.469C>T	p.Pro157Ser	missense_variant	Exon 5 of 16	1	NM_007348.4	ENSP00000356919.3

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

18003

AN:

151992

Hom.:

1598

Cov.:

show subpopulations

Gnomad AFR

AF:

0.135

Gnomad AMI

AF:

0.0275

Gnomad AMR

AF:

0.268

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.313

Gnomad SAS

AF:

0.0940

Gnomad FIN

AF:

0.0692

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0712

Gnomad OTH

AF:

0.122

GnomAD2 exomes

AF:

0.149

AC:

36827

AN:

247808

AF XY:

0.133

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.450

Gnomad ASJ exome

AF:

0.0973

Gnomad EAS exome

AF:

0.310

Gnomad FIN exome

AF:

0.0690

Gnomad NFE exome

AF:

0.0718

Gnomad OTH exome

AF:

0.116

GnomAD4 exome

AF:

0.0913

AC:

132966

AN:

1455610

Hom.:

11023

Cov.:

AF XY:

0.0897

AC XY:

64986

AN XY:

724352

show subpopulations

African (AFR)

AF:

0.133

AC:

4430

AN:

33288

American (AMR)

AF:

0.429

AC:

18934

AN:

44104

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

2723

AN:

25998

East Asian (EAS)

AF:

0.342

AC:

13458

AN:

39392

South Asian (SAS)

AF:

0.0855

AC:

7353

AN:

85958

European-Finnish (FIN)

AF:

0.0650

AC:

3347

AN:

51522

Middle Eastern (MID)

AF:

0.0957

AC:

551

AN:

5758

European-Non Finnish (NFE)

AF:

0.0685

AC:

76039

AN:

1109390

Other (OTH)

AF:

0.102

AC:

6131

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

5199

10398

15598

20797

25996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3174

6348

9522

12696

15870

<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:

0.119

AC:

18047

AN:

152110

Hom.:

1613

Cov.:

AF XY:

0.122

AC XY:

9047

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.136

AC:

5623

AN:

41464

American (AMR)

AF:

0.269

AC:

4110

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

352

AN:

3472

East Asian (EAS)

AF:

0.313

AC:

1616

AN:

5160

South Asian (SAS)

AF:

0.0933

AC:

450

AN:

4824

European-Finnish (FIN)

AF:

0.0692

AC:

733

AN:

10588

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0712

AC:

4841

AN:

68008

Other (OTH)

AF:

0.127

AC:

268

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

769

1538

2308

3077

3846

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

200

400

600

800

1000

<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:

0.100

Hom.:

2659

Bravo

AF:

0.140

TwinsUK

AF:

0.0707

AC:

262

ALSPAC

AF:

0.0739

AC:

285

ESP6500AA

AF:

0.130

AC:

573

ESP6500EA

AF:

0.0736

AC:

633

ExAC

AF:

0.137

AC:

16680

Asia WGS

AF:

0.255

AC:

888

AN:

3476

EpiCase

AF:

0.0733

EpiControl

AF:

0.0755

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

0.075

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.12

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

PhyloP100

0.45

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.42

REVEL

Benign

0.059

Sift

Benign

0.21

Sift4G

Benign

0.65

Polyphen

0.031

Vest4

0.039

MPC

0.15

ClinPred

0.0019

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.028

gMVP

0.30

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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