rs11581556

Variant names:

• chr1-161823822-G-A
• rs11581556
• NM_007348.4:c.1187+2661G>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.1187+2661G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 152,090 control chromosomes in the GnomAD database, including 3,925 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 0.20 (3925 hom., cov: 32)
• Consequence: ATF6 NM_007348.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.114
• Publications: 9 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.276 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.1187+2661G>A		intron	N/A	NP_031374.2
	ATF6	NM_001437597.1		c.1187+2661G>A		intron	N/A	NP_001424526.1
	ATF6	NM_001410890.1		c.1187+2661G>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.1187+2661G>A		intron	N/A	ENSP00000356919.3
	ATF6	ENST00000681492.1		c.1187+2661G>A		intron	N/A	ENSP00000506139.1
	ATF6	ENST00000680688.1		c.1187+2661G>A		intron	N/A	ENSP00000504865.1

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30904 AN: 151972 Hom.: 3927 Cov.: 32

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.209

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

GnomAD4 genome AF: 0.203 AC: 30896 AN: 152090 Hom.: 3925 Cov.: 32 AF XY: 0.203 AC XY: 15126 AN XY: 74340

African (AFR) AF: 0.0498 AC: 2066 AN: 41520

American (AMR) AF: 0.191 AC: 2921 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 745 AN: 3472

East Asian (EAS) AF: 0.276 AC: 1425 AN: 5160

South Asian (SAS) AF: 0.162 AC: 782 AN: 4824

European-Finnish (FIN) AF: 0.296 AC: 3129 AN: 10560

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18982 AN: 67956

Other (OTH) AF: 0.207 AC: 437 AN: 2108

Alfa AF: 0.253 Hom.: 8584

Bravo AF: 0.191

Asia WGS AF: 0.202 AC: 700 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.0
DANN	Benign	0.81
PhyloP100		0.11
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: rs11581556; hg19: chr1-161793612;