rs2271012

chr1-161784051-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_007348.4(ATF6):c.309G>A(p.Ser103=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0939 in 1,610,374 control chromosomes in the GnomAD database, including 12,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1618 hom., cov: 31)
  • Exomes 𝑓: 0.091 (11144 hom.)
• Consequence: ATF6 NM_007348.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.513

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-161784051-G-A is Benign according to our data. Variant chr1-161784051-G-A is described in ClinVar as [Benign]. Clinvar id is 1164405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.513 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATF6	NM_007348.4	c.309G>A	p.Ser103=	synonymous_variant	4/16	ENST00000367942.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATF6	ENST00000367942.4	c.309G>A	p.Ser103=	synonymous_variant	4/16	1	NM_007348.4	A2

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18002 AN: 151902 Hom.: 1603 Cov.: 31

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.0934

Gnomad FIN AF: 0.0691

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0712

Gnomad OTH AF: 0.122

GnomAD3 exomes AF: 0.150 AC: 37630 AN: 251124 Hom.: 5532 AF XY: 0.134 AC XY: 18216 AN XY: 135730

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.453

Gnomad ASJ exome AF: 0.0985

Gnomad EAS exome AF: 0.312

Gnomad SAS exome AF: 0.0868

Gnomad FIN exome AF: 0.0702

Gnomad NFE exome AF: 0.0722

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.0914 AC: 133245 AN: 1458354 Hom.: 11144 Cov.: 30 AF XY: 0.0898 AC XY: 65134 AN XY: 725702

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.432

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.342

Gnomad4 SAS exome AF: 0.0857

Gnomad4 FIN exome AF: 0.0660

Gnomad4 NFE exome AF: 0.0682

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.119 AC: 18046 AN: 152020 Hom.: 1618 Cov.: 31 AF XY: 0.122 AC XY: 9029 AN XY: 74276

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.314

Gnomad4 SAS AF: 0.0926

Gnomad4 FIN AF: 0.0691

Gnomad4 NFE AF: 0.0712

Gnomad4 OTH AF: 0.128

Alfa AF: 0.101 Hom.: 933

Bravo AF: 0.140

Asia WGS AF: 0.255 AC: 889 AN: 3478

EpiCase AF: 0.0734

EpiControl AF: 0.0756

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.5
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs2271012; hg19: chr1-161753841; COSMIC: COSV63407616;