rs2134697

Variant names:

• chr1-161811189-G-A
• rs2134697
• NM_007348.4:c.910-8444G>A

Variant summary

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

The NM_007348.4(ATF6):​c.910-8444G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 152,102 control chromosomes in the GnomAD database, including 33,235 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 0.63 (33235 hom., cov: 32)
• Consequence: ATF6 NM_007348.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200
• Publications: 10 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.742 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6	NM_007348.4	MANE Select	c.910-8444G>A		intron	N/A	NP_031374.2
	ATF6	NM_001437597.1		c.910-8444G>A		intron	N/A	NP_001424526.1
	ATF6	NM_001410890.1		c.910-8444G>A		intron	N/A	NP_001397819.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6	ENST00000367942.4	TSL:1 MANE Select	c.910-8444G>A		intron	N/A	ENSP00000356919.3
	ATF6	ENST00000681492.1		c.910-8444G>A		intron	N/A	ENSP00000506139.1
	ATF6	ENST00000680688.1		c.910-8444G>A		intron	N/A	ENSP00000504865.1

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96470 AN: 151984 Hom.: 33214 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.753

Gnomad ASJ AF: 0.791

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.664

Gnomad FIN AF: 0.795

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.746

Gnomad OTH AF: 0.685

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

GnomAD4 genome AF: 0.635 AC: 96523 AN: 152102 Hom.: 33235 Cov.: 32 AF XY: 0.639 AC XY: 47495 AN XY: 74358

African (AFR) AF: 0.345 AC: 14312 AN: 41460

American (AMR) AF: 0.754 AC: 11521 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.791 AC: 2746 AN: 3472

East Asian (EAS) AF: 0.639 AC: 3310 AN: 5180

South Asian (SAS) AF: 0.665 AC: 3206 AN: 4822

European-Finnish (FIN) AF: 0.795 AC: 8414 AN: 10584

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.746 AC: 50746 AN: 67986

Other (OTH) AF: 0.688 AC: 1452 AN: 2112

Alfa AF: 0.715 Hom.: 175117

Bravo AF: 0.623

Asia WGS AF: 0.696 AC: 2419 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.6
DANN	Benign	0.80
PhyloP100		0.020
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2134697; hg19: chr1-161780979;