1-161957389-G-C

Variant names:

• chr1-161957389-G-C
• rs7522210
• NM_007348.4:c.1805-1057G>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.1805-1057G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 151,966 control chromosomes in the GnomAD database, including 32,398 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 0.64 (32398 hom., cov: 31)
• Consequence: ATF6 NM_007348.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0860
• Publications: 3 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATF6	NM_007348.4	c.1805-1057G>C		intron_variant	Intron 15 of 15	ENST00000367942.4	NP_031374.2
ATF6	NM_001437597.1	c.1862-1057G>C		intron_variant	Intron 15 of 15		NP_001424526.1
ATF6	NM_001410890.1	c.1802-1057G>C		intron_variant	Intron 15 of 15		NP_001397819.1
ATF6	XM_011509309.1	c.1859-1057G>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.1805-1057G>C		intron_variant	Intron 15 of 15	1	NM_007348.4	ENSP00000356919.3

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96746 AN: 151850 Hom.: 32382 Cov.: 31

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.719

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.806

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.751

Gnomad OTH AF: 0.647

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

GnomAD4 genome AF: 0.637 AC: 96794 AN: 151966 Hom.: 32398 Cov.: 31 AF XY: 0.635 AC XY: 47149 AN XY: 74262

African (AFR) AF: 0.455 AC: 18826 AN: 41390

American (AMR) AF: 0.536 AC: 8195 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 2494 AN: 3470

East Asian (EAS) AF: 0.519 AC: 2686 AN: 5172

South Asian (SAS) AF: 0.593 AC: 2846 AN: 4796

European-Finnish (FIN) AF: 0.806 AC: 8513 AN: 10556

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.751 AC: 51068 AN: 67972

Other (OTH) AF: 0.641 AC: 1356 AN: 2114

Alfa AF: 0.688 Hom.: 4572

Bravo AF: 0.609

Asia WGS AF: 0.524 AC: 1824 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.33
PhyloP100		-0.086
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: rs7522210; hg19: chr1-161927179;