rs6687226

Variant names:

• chr1-161921766-A-C
• rs6687226
• NM_007348.4:c.1804+9386A>C

Variant summary

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

The NM_007348.4(ATF6):​c.1804+9386A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.93 in 152,300 control chromosomes in the GnomAD database, including 66,011 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 0.93 (66011 hom., cov: 32)
• Consequence: ATF6 NM_007348.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.28
• Publications: 6 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATF6	NM_007348.4	c.1804+9386A>C		intron_variant	Intron 15 of 15	ENST00000367942.4	NP_031374.2
ATF6	NM_001437597.1	c.1861+9386A>C		intron_variant	Intron 15 of 15		NP_001424526.1
ATF6	NM_001410890.1	c.1801+9386A>C		intron_variant	Intron 15 of 15		NP_001397819.1
ATF6	XM_011509309.1	c.1858+9386A>C		intron_variant	Intron 15 of 15		XP_011507611.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATF6	ENST00000367942.4	c.1804+9386A>C		intron_variant	Intron 15 of 15	1	NM_007348.4	ENSP00000356919.3

Frequencies

GnomAD3 genomes AF: 0.930 AC: 141545 AN: 152182 Hom.: 65950 Cov.: 32

Gnomad AFR AF: 0.968

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.927

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.924

Gnomad FIN AF: 0.919

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.906

Gnomad OTH AF: 0.944

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

GnomAD4 genome AF: 0.930 AC: 141665 AN: 152300 Hom.: 66011 Cov.: 32 AF XY: 0.931 AC XY: 69325 AN XY: 74474

African (AFR) AF: 0.968 AC: 40239 AN: 41576

American (AMR) AF: 0.927 AC: 14186 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.950 AC: 3298 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5183 AN: 5190

South Asian (SAS) AF: 0.924 AC: 4458 AN: 4824

European-Finnish (FIN) AF: 0.919 AC: 9740 AN: 10604

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.906 AC: 61637 AN: 68016

Other (OTH) AF: 0.944 AC: 1996 AN: 2114

Alfa AF: 0.916 Hom.: 10745

Bravo AF: 0.933

Asia WGS AF: 0.967 AC: 3361 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.67
DANN	Benign	0.68
PhyloP100		-2.3
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: rs6687226; hg19: chr1-161891556;