Genetic Variant ATF6:p.Pro90Pro (chr1-161784012-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_007348.4(ATF6):c.270T>C(p.Pro90Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0894 in 1,609,026 control chromosomes in the GnomAD database, including 11,958 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.097 ( 1268 hom., cov: 31)

Exomes 𝑓: 0.089 ( 10690 hom. )

Consequence

ATF6
NM_007348.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.840

Publications

21 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: G2P, Labcorp Genetics (formerly Invitae)
ATF6-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
achromatopsia
Inheritance: Unknown, AR Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 1-161784012-T-C is Benign according to our data. Variant chr1-161784012-T-C is described in ClinVar as Benign. ClinVar VariationId is 1164404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007348.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATF6	NM_007348.4	MANE Select	c.270T>C	p.Pro90Pro	synonymous	Exon 4 of 16	NP_031374.2	P18850
ATF6	NM_001437597.1		c.270T>C	p.Pro90Pro	synonymous	Exon 4 of 16	NP_001424526.1	A0A7P0Z421
ATF6	NM_001410890.1		c.270T>C	p.Pro90Pro	synonymous	Exon 4 of 16	NP_001397819.1	A0A7P0TAF2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATF6	ENST00000367942.4	TSL:1 MANE Select	c.270T>C	p.Pro90Pro	synonymous	Exon 4 of 16	ENSP00000356919.3	P18850
ATF6	ENST00000681492.1		c.270T>C	p.Pro90Pro	synonymous	Exon 4 of 17	ENSP00000506139.1	A0A7P0TAH1
ATF6	ENST00000951832.1		c.270T>C	p.Pro90Pro	synonymous	Exon 4 of 17	ENSP00000621891.1

Frequencies

GnomAD3 genomes

AF:

0.0964

AC:

14660

AN:

152048

Hom.:

1255

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0581

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.262

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.314

Gnomad SAS

AF:

0.0928

Gnomad FIN

AF:

0.0684

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0711

Gnomad OTH

AF:

0.107

GnomAD2 exomes

AF:

0.144

AC:

36112

AN:

251158

AF XY:

0.130

show subpopulations

Gnomad AFR exome

AF:

0.0551

Gnomad AMR exome

AF:

0.448

Gnomad ASJ exome

AF:

0.0984

Gnomad EAS exome

AF:

0.312

Gnomad FIN exome

AF:

0.0703

Gnomad NFE exome

AF:

0.0719

Gnomad OTH exome

AF:

0.113

GnomAD4 exome

AF:

0.0886

AC:

129147

AN:

1456860

Hom.:

10690

Cov.:

AF XY:

0.0874

AC XY:

63391

AN XY:

725016

show subpopulations

African (AFR)

AF:

0.0568

AC:

1897

AN:

33388

American (AMR)

AF:

0.427

AC:

19077

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

2730

AN:

26060

East Asian (EAS)

AF:

0.342

AC:

13519

AN:

39536

South Asian (SAS)

AF:

0.0853

AC:

7346

AN:

86118

European-Finnish (FIN)

AF:

0.0658

AC:

3515

AN:

53382

Middle Eastern (MID)

AF:

0.0915

AC:

527

AN:

5760

European-Non Finnish (NFE)

AF:

0.0675

AC:

74792

AN:

1107764

Other (OTH)

AF:

0.0954

AC:

5744

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

4840

9680

14519

19359

24199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3066

6132

9198

12264

15330

<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:

0.0966

AC:

14693

AN:

152166

Hom.:

1268

Cov.:

AF XY:

0.100

AC XY:

7457

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0582

AC:

2416

AN:

41532

American (AMR)

AF:

0.263

AC:

4010

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

352

AN:

3468

East Asian (EAS)

AF:

0.313

AC:

1622

AN:

5176

South Asian (SAS)

AF:

0.0921

AC:

444

AN:

4822

European-Finnish (FIN)

AF:

0.0684

AC:

726

AN:

10610

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0711

AC:

4831

AN:

67990

Other (OTH)

AF:

0.113

AC:

238

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

601

1203

1804

2406

3007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<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:

0.0805

Hom.:

827

Bravo

AF:

0.115

Asia WGS

AF:

0.247

AC:

860

AN:

3478

EpiCase

AF:

0.0732

EpiControl

AF:

0.0753

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Achromatopsia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.7

(source)

DANN

Benign

0.79

PhyloP100

0.84

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over