1-161826106-G-A

Variant names:

• chr1-161826106-G-A
• rs10918029
• NM_007348.4:c.1187+4945G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007348.4(ATF6):​c.1187+4945G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 152,082 control chromosomes in the GnomAD database, including 2,715 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 0.15 (2715 hom., cov: 32)
• Consequence: ATF6 NM_007348.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.354
• 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=-0.67).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 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.1187+4945G>A		intron	N/A	NP_031374.2
	ATF6	NM_001437597.1		c.1187+4945G>A		intron	N/A	NP_001424526.1
	ATF6	NM_001410890.1		c.1187+4945G>A		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.1187+4945G>A		intron	N/A	ENSP00000356919.3
	ATF6	ENST00000681492.1		c.1187+4945G>A		intron	N/A	ENSP00000506139.1
	ATF6	ENST00000680688.1		c.1187+4945G>A		intron	N/A	ENSP00000504865.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23149 AN: 151964 Hom.: 2699 Cov.: 32

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0711

Gnomad ASJ AF: 0.0384

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.0515

Gnomad FIN AF: 0.0838

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0896

Gnomad OTH AF: 0.112

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

GnomAD4 genome AF: 0.153 AC: 23195 AN: 152082 Hom.: 2715 Cov.: 32 AF XY: 0.148 AC XY: 10989 AN XY: 74352

African (AFR) AF: 0.323 AC: 13401 AN: 41442

American (AMR) AF: 0.0710 AC: 1085 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0384 AC: 133 AN: 3468

East Asian (EAS) AF: 0.204 AC: 1058 AN: 5178

South Asian (SAS) AF: 0.0511 AC: 247 AN: 4830

European-Finnish (FIN) AF: 0.0838 AC: 885 AN: 10556

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0896 AC: 6095 AN: 68000

Other (OTH) AF: 0.112 AC: 237 AN: 2114

Alfa AF: 0.101 Hom.: 4413

Bravo AF: 0.159

Asia WGS AF: 0.118 AC: 412 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		-0.35
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: rs10918029; hg19: chr1-161795896;