rs1136046

Positions:

• chr1-161958981-G-A
• chr1-161958981-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007348.4(ATF6):​c.*327G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 201,226 control chromosomes in the GnomAD database, including 6,151 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 0.22 (4965 hom., cov: 32)
  • Exomes 𝑓: 0.18 (1186 hom.)
• Consequence: ATF6 NM_007348.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.171

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATF6	NM_007348.4	c.*327G>A		3_prime_UTR_variant	16/16	ENST00000367942.4	NP_031374.2
ATF6	NM_001410890.1	c.*327G>A		3_prime_UTR_variant	16/16		NP_001397819.1
ATF6	XM_011509308.1	c.*327G>A		3_prime_UTR_variant	16/16		XP_011507610.1
ATF6	XM_011509309.1	c.*327G>A		3_prime_UTR_variant	16/16		XP_011507611.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATF6	ENST00000367942.4	c.*327G>A		3_prime_UTR_variant	16/16	1	NM_007348.4	ENSP00000356919	A2

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33052 AN: 151860 Hom.: 4950 Cov.: 32

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.0981

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.182 AC: 8948 AN: 49248 Hom.: 1186 Cov.: 0 AF XY: 0.179 AC XY: 4478 AN XY: 25052

Gnomad4 AFR exome AF: 0.386

Gnomad4 AMR exome AF: 0.420

Gnomad4 ASJ exome AF: 0.190

Gnomad4 EAS exome AF: 0.448

Gnomad4 SAS exome AF: 0.242

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.119

Gnomad4 OTH exome AF: 0.185

GnomAD4 genome AF: 0.218 AC: 33102 AN: 151978 Hom.: 4965 Cov.: 32 AF XY: 0.222 AC XY: 16527 AN XY: 74304

Gnomad4 AFR AF: 0.373

Gnomad4 AMR AF: 0.335

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.363

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.0981

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.224

Alfa AF: 0.144 Hom.: 2853

Bravo AF: 0.244

Asia WGS AF: 0.339 AC: 1181 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	4.3
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs1136046; hg19: chr1-161928771;