rs4657121

Variant names:

• chr1-161913293-G-A
• rs4657121
• NM_007348.4:c.1804+913G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-161913293-G-A
• chr1-161913293-G-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+913G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 152,042 control chromosomes in the GnomAD database, including 4,078 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 0.21 (4078 hom., cov: 32)
• Consequence: ATF6 NM_007348.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.269
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATF6	NM_007348.4	c.1804+913G>A		intron_variant	Intron 15 of 15	ENST00000367942.4	NP_031374.2
ATF6	NM_001437597.1	c.1861+913G>A		intron_variant	Intron 15 of 15		NP_001424526.1
ATF6	NM_001410890.1	c.1801+913G>A		intron_variant	Intron 15 of 15		NP_001397819.1
ATF6	XM_011509309.1	c.1858+913G>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.1804+913G>A		intron_variant	Intron 15 of 15	1	NM_007348.4	ENSP00000356919.3

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31937 AN: 151924 Hom.: 4081 Cov.: 32

Gnomad AFR AF: 0.0638

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.210 AC: 31928 AN: 152042 Hom.: 4078 Cov.: 32 AF XY: 0.211 AC XY: 15646 AN XY: 74318

African (AFR) AF: 0.0636 AC: 2639 AN: 41494

American (AMR) AF: 0.198 AC: 3026 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 758 AN: 3466

East Asian (EAS) AF: 0.276 AC: 1427 AN: 5176

South Asian (SAS) AF: 0.165 AC: 795 AN: 4812

European-Finnish (FIN) AF: 0.304 AC: 3206 AN: 10562

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.283 AC: 19215 AN: 67942

Other (OTH) AF: 0.213 AC: 449 AN: 2106

Alfa AF: 0.227 Hom.: 2846

Bravo AF: 0.198

Asia WGS AF: 0.201 AC: 698 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.0
DANN	Benign	0.44
PhyloP100		0.27
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: rs4657121; hg19: chr1-161883083;