1-161887406-A-G

Variant names:

• chr1-161887406-A-G
• rs4532807
• NM_007348.4:c.1719+24094A>G

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+24094A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,126 control chromosomes in the GnomAD database, including 1,898 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 0.11 (1898 hom., cov: 32)
• Consequence: ATF6 NM_007348.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.169
• Publications: 0 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6	NM_007348.4	MANE Select	c.1719+24094A>G		intron	N/A	NP_031374.2
	ATF6	NM_001437597.1		c.1776+24094A>G		intron	N/A	NP_001424526.1
	ATF6	NM_001410890.1		c.1716+24094A>G		intron	N/A	NP_001397819.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6	ENST00000367942.4	TSL:1 MANE Select	c.1719+24094A>G		intron	N/A	ENSP00000356919.3
	ATF6	ENST00000680180.1		n.1994A>G		non_coding_transcript_exon	Exon 16 of 16
	ATF6	ENST00000681187.1		n.1904A>G		non_coding_transcript_exon	Exon 15 of 15

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16882 AN: 152006 Hom.: 1893 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0636

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.0386

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0360

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.111 AC: 16904 AN: 152126 Hom.: 1898 Cov.: 32 AF XY: 0.111 AC XY: 8250 AN XY: 74406

African (AFR) AF: 0.288 AC: 11942 AN: 41464

American (AMR) AF: 0.0635 AC: 970 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 204 AN: 3468

East Asian (EAS) AF: 0.0383 AC: 198 AN: 5170

South Asian (SAS) AF: 0.120 AC: 576 AN: 4820

European-Finnish (FIN) AF: 0.0289 AC: 307 AN: 10608

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0360 AC: 2451 AN: 67996

Other (OTH) AF: 0.104 AC: 219 AN: 2112

Alfa AF: 0.0587 Hom.: 278

Bravo AF: 0.120

Asia WGS AF: 0.0780 AC: 272 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.56
DANN	Benign	0.29
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4532807; hg19: chr1-161857196;