rs2271012

Variant names:

• chr1-161784051-G-A
• rs2271012
• NM_007348.4:c.309G>A
• ATF6 p.Ser103Ser

Your query was ambiguous. Multiple possible variants found:

• chr1-161784051-G-A
• chr1-161784051-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_007348.4(ATF6):​c.309G>A​(p.Ser103Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0939 in 1,610,374 control chromosomes in the GnomAD database, including 12,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S103S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1618 hom., cov: 31)
  • Exomes 𝑓: 0.091 (11144 hom.)
• Consequence: ATF6 NM_007348.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.513
• Publications: 17 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: Labcorp Genetics (formerly Invitae), G2P
• ATF6-related retinopathy

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

  Inheritance: AR, Unknown 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-161784051-G-A is Benign according to our data. Variant chr1-161784051-G-A is described in ClinVar as Benign. ClinVar VariationId is 1164405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.513 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.302 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.309G>A	p.Ser103Ser	synonymous	Exon 4 of 16	NP_031374.2	P18850
	ATF6	NM_001437597.1		c.309G>A	p.Ser103Ser	synonymous	Exon 4 of 16	NP_001424526.1	A0A7P0Z421
	ATF6	NM_001410890.1		c.309G>A	p.Ser103Ser	synonymous	Exon 4 of 16	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.309G>A	p.Ser103Ser	synonymous	Exon 4 of 16	ENSP00000356919.3	P18850
	ATF6	ENST00000681492.1		c.309G>A	p.Ser103Ser	synonymous	Exon 4 of 17	ENSP00000506139.1	A0A7P0TAH1
	ATF6	ENST00000951832.1		c.309G>A	p.Ser103Ser	synonymous	Exon 4 of 17	ENSP00000621891.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18002 AN: 151902 Hom.: 1603 Cov.: 31

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.0934

Gnomad FIN AF: 0.0691

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0712

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.150 AC: 37630 AN: 251124 AF XY: 0.134

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.453

Gnomad ASJ exome AF: 0.0985

Gnomad EAS exome AF: 0.312

Gnomad FIN exome AF: 0.0702

Gnomad NFE exome AF: 0.0722

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.0914 AC: 133245 AN: 1458354 Hom.: 11144 Cov.: 30 AF XY: 0.0898 AC XY: 65134 AN XY: 725702

African (AFR) AF: 0.133 AC: 4449 AN: 33410

American (AMR) AF: 0.432 AC: 19305 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2747 AN: 26098

East Asian (EAS) AF: 0.342 AC: 13531 AN: 39554

South Asian (SAS) AF: 0.0857 AC: 7387 AN: 86150

European-Finnish (FIN) AF: 0.0660 AC: 3522 AN: 53384

Middle Eastern (MID) AF: 0.0955 AC: 550 AN: 5760

European-Non Finnish (NFE) AF: 0.0682 AC: 75622 AN: 1109082

Other (OTH) AF: 0.102 AC: 6132 AN: 60268

GnomAD4 genome AF: 0.119 AC: 18046 AN: 152020 Hom.: 1618 Cov.: 31 AF XY: 0.122 AC XY: 9029 AN XY: 74276

African (AFR) AF: 0.136 AC: 5631 AN: 41464

American (AMR) AF: 0.269 AC: 4097 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 350 AN: 3468

East Asian (EAS) AF: 0.314 AC: 1627 AN: 5174

South Asian (SAS) AF: 0.0926 AC: 446 AN: 4814

European-Finnish (FIN) AF: 0.0691 AC: 729 AN: 10552

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0712 AC: 4842 AN: 67984

Other (OTH) AF: 0.128 AC: 270 AN: 2112

Alfa AF: 0.102 Hom.: 1245

Bravo AF: 0.140

Asia WGS AF: 0.255 AC: 889 AN: 3478

EpiCase AF: 0.0734

EpiControl AF: 0.0756

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Achromatopsia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.5
DANN	Benign	0.72
PhyloP100		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2271012;

hg19: chr1-161753841;

COSMIC: COSV63407616;