1-161791486-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007348.4(ATF6):c.433G>C(p.Ala145Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0902 in 1,611,170 control chromosomes in the GnomAD database, including 12,011 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A145E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.097 ( 1272 hom., cov: 32)

Exomes 𝑓: 0.090 ( 10739 hom. )

Consequence

ATF6
NM_007348.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.181

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.8853626E-4).

BP6

Variant 1-161791486-G-C is Benign according to our data. Variant chr1-161791486-G-C is described in ClinVar as [Benign]. Clinvar id is 1164406.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.433G>C	p.Ala145Pro	missense_variant	Exon 5 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.433G>C	p.Ala145Pro	missense_variant	Exon 5 of 16	1	NM_007348.4	ENSP00000356919.3		P18850

Frequencies

GnomAD3 genomes

AF:

0.0966

AC:

14687

AN:

152072

Hom.:

1259

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0582

Gnomad AMI

AF:

0.0275

Gnomad AMR

AF:

0.262

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.313

Gnomad SAS

AF:

0.0935

Gnomad FIN

AF:

0.0694

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0711

Gnomad OTH

AF:

0.107

GnomAD3 exomes

AF:

0.143

AC:

35899

AN:

250206

Hom.:

5308

AF XY:

0.130

AC XY:

17563

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.0551

Gnomad AMR exome

AF:

0.448

Gnomad ASJ exome

AF:

0.0979

Gnomad EAS exome

AF:

0.311

Gnomad SAS exome

AF:

0.0861

Gnomad FIN exome

AF:

0.0697

Gnomad NFE exome

AF:

0.0718

Gnomad OTH exome

AF:

0.113

GnomAD4 exome

AF:

0.0895

AC:

130642

AN:

1458980

Hom.:

10739

Cov.:

AF XY:

0.0882

AC XY:

64058

AN XY:

725914

show subpopulations

Gnomad4 AFR exome

AF:

0.0574

Gnomad4 AMR exome

AF:

0.427

Gnomad4 ASJ exome

AF:

0.105

Gnomad4 EAS exome

AF:

0.342

Gnomad4 SAS exome

AF:

0.0855

Gnomad4 FIN exome

AF:

0.0650

Gnomad4 NFE exome

AF:

0.0687

Gnomad4 OTH exome

AF:

0.0963

GnomAD4 genome

AF:

0.0967

AC:

14720

AN:

152190

Hom.:

1272

Cov.:

AF XY:

0.100

AC XY:

7476

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0583

Gnomad4 AMR

AF:

0.264

Gnomad4 ASJ

AF:

0.101

Gnomad4 EAS

AF:

0.313

Gnomad4 SAS

AF:

0.0928

Gnomad4 FIN

AF:

0.0694

Gnomad4 NFE

AF:

0.0711

Gnomad4 OTH

AF:

0.113

Alfa

AF:

0.0873

Hom.:

731

Bravo

AF:

0.115

TwinsUK

AF:

0.0707

AC:

262

ALSPAC

AF:

0.0739

AC:

285

ESP6500AA

AF:

0.0592

AC:

261

ESP6500EA

AF:

0.0731

AC:

629

ExAC

AF:

0.130

AC:

15807

Asia WGS

AF:

0.247

AC:

860

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

0.081

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

5.0

DANN

Benign

0.94

DEOGEN2

Benign

0.050

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.45

MetaRNN

Benign

0.00059

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.32

PROVEAN

Benign

0.45

REVEL

Benign

0.041

Sift

Benign

0.36

Sift4G

Benign

0.43

Polyphen

0.0

Vest4

0.036

MPC

0.19

ClinPred

0.0010

GERP RS

0.78

Varity_R

0.041

gMVP

0.19

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

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