1-161975629-C-A

Variant names:

• chr1-161975629-C-A
• rs1962508
• ENST00000681738.1:n.*57-297C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000681738.1(ATF6):​n.*57-297C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 152,072 control chromosomes in the GnomAD database, including 19,806 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (19806 hom., cov: 32)
• Consequence: ATF6 ENST00000681738.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATF6	ENST00000681738.1	n.*57-297C>A		intron_variant	Intron 16 of 16			ENSP00000505025.1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67814 AN: 151954 Hom.: 19744 Cov.: 32

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.559

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.407

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.447 AC: 67946 AN: 152072 Hom.: 19806 Cov.: 32 AF XY: 0.446 AC XY: 33143 AN XY: 74354

African (AFR) AF: 0.823 AC: 34136 AN: 41484

American (AMR) AF: 0.451 AC: 6886 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 837 AN: 3464

East Asian (EAS) AF: 0.558 AC: 2880 AN: 5164

South Asian (SAS) AF: 0.360 AC: 1735 AN: 4826

European-Finnish (FIN) AF: 0.249 AC: 2630 AN: 10566

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17746 AN: 67974

Other (OTH) AF: 0.412 AC: 871 AN: 2114

Alfa AF: 0.369 Hom.: 5010

Bravo AF: 0.478

Asia WGS AF: 0.523 AC: 1819 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.11
DANN	Benign	0.70
PhyloP100		-1.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1962508; hg19: chr1-161945419;