chr1-161945711-G-A

Variant names:

• chr1-161945711-G-A
• rs10918270
• NM_007348.4:c.1805-12735G>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.1805-12735G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 152,012 control chromosomes in the GnomAD database, including 10,630 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 0.37 (10630 hom., cov: 32)
• Consequence: ATF6 NM_007348.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 14 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATF6	NM_007348.4	c.1805-12735G>A		intron_variant	Intron 15 of 15	ENST00000367942.4	NP_031374.2
ATF6	NM_001437597.1	c.1862-12735G>A		intron_variant	Intron 15 of 15		NP_001424526.1
ATF6	NM_001410890.1	c.1802-12735G>A		intron_variant	Intron 15 of 15		NP_001397819.1
ATF6	XM_011509309.1	c.1859-12735G>A		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.1805-12735G>A		intron_variant	Intron 15 of 15	1	NM_007348.4	ENSP00000356919.3

Frequencies

GnomAD3 genomes AF: 0.369 AC: 56090 AN: 151894 Hom.: 10613 Cov.: 32

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.365

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

GnomAD4 genome AF: 0.369 AC: 56136 AN: 152012 Hom.: 10630 Cov.: 32 AF XY: 0.368 AC XY: 27348 AN XY: 74286

African (AFR) AF: 0.335 AC: 13878 AN: 41482

American (AMR) AF: 0.283 AC: 4317 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1600 AN: 3464

East Asian (EAS) AF: 0.242 AC: 1256 AN: 5186

South Asian (SAS) AF: 0.372 AC: 1790 AN: 4810

European-Finnish (FIN) AF: 0.470 AC: 4954 AN: 10538

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27197 AN: 67944

Other (OTH) AF: 0.365 AC: 772 AN: 2116

Alfa AF: 0.383 Hom.: 32612

Bravo AF: 0.352

Asia WGS AF: 0.291 AC: 1014 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.26
DANN	Benign	0.41
PhyloP100		-1.1
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: rs10918270; hg19: chr1-161915501;