NM_007348.4:c.1719+16283A>C

Variant names:

• chr1-161879595-A-C
• rs2340721
• NM_007348.4:c.1719+16283A>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.1719+16283A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 151,900 control chromosomes in the GnomAD database, including 22,497 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 0.49 (22497 hom., cov: 31)
• Consequence: ATF6 NM_007348.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.145
• Publications: 12 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: G2P, Labcorp Genetics (formerly Invitae)
• ATF6-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• achromatopsia

  Inheritance: Unknown, AR Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007348.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6	NM_007348.4	MANE Select	c.1719+16283A>C		intron	N/A	NP_031374.2	P18850
	ATF6	NM_001437597.1		c.1776+16283A>C		intron	N/A	NP_001424526.1	A0A7P0Z421
	ATF6	NM_001410890.1		c.1716+16283A>C		intron	N/A	NP_001397819.1	A0A7P0TAF2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6	ENST00000367942.4	TSL:1 MANE Select	c.1719+16283A>C		intron	N/A	ENSP00000356919.3	P18850
	ATF6	ENST00000681492.1		c.1809+8534A>C		intron	N/A	ENSP00000506139.1	A0A7P0TAH1
	ATF6	ENST00000951832.1		c.1806+8534A>C		intron	N/A	ENSP00000621891.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 74915 AN: 151782 Hom.: 22497 Cov.: 31

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.722

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.662

Gnomad OTH AF: 0.543

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

GnomAD4 genome AF: 0.493 AC: 74910 AN: 151900 Hom.: 22497 Cov.: 31 AF XY: 0.496 AC XY: 36823 AN XY: 74240

African (AFR) AF: 0.152 AC: 6318 AN: 41450

American (AMR) AF: 0.473 AC: 7210 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 2419 AN: 3468

East Asian (EAS) AF: 0.325 AC: 1666 AN: 5134

South Asian (SAS) AF: 0.582 AC: 2801 AN: 4810

European-Finnish (FIN) AF: 0.722 AC: 7629 AN: 10562

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.662 AC: 44972 AN: 67924

Other (OTH) AF: 0.538 AC: 1137 AN: 2114

Alfa AF: 0.419 Hom.: 1544

Bravo AF: 0.459

Asia WGS AF: 0.421 AC: 1465 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.4
DANN	Benign	0.57
PhyloP100		0.14
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: rs2340721; hg19: chr1-161849385;