rs2070150

Variant names:

• chr1-161791486-G-C
• rs2070150
• NM_007348.4:c.433G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-161791486-G-C
• chr1-161791486-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007348.4(ATF6):​c.433G>C​(p.Ala145Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0902 in 1,611,170 control chromosomes in the GnomAD database, including 12,011 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A145E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.097 (1272 hom., cov: 32)
  • Exomes 𝑓: 0.090 (10739 hom.)
• Consequence: ATF6 NM_007348.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.181
• Publications: 31 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.8853626E-4).
• BP6: Variant 1-161791486-G-C is Benign according to our data. Variant chr1-161791486-G-C is described in ClinVar as Benign. ClinVar VariationId is 1164406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.3 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.433G>C	p.Ala145Pro	missense	Exon 5 of 16	NP_031374.2	P18850
	ATF6	NM_001437597.1		c.433G>C	p.Ala145Pro	missense	Exon 5 of 16	NP_001424526.1	A0A7P0Z421
	ATF6	NM_001410890.1		c.433G>C	p.Ala145Pro	missense	Exon 5 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.433G>C	p.Ala145Pro	missense	Exon 5 of 16	ENSP00000356919.3	P18850
	ATF6	ENST00000681492.1		c.433G>C	p.Ala145Pro	missense	Exon 5 of 17	ENSP00000506139.1	A0A7P0TAH1
	ATF6	ENST00000951832.1		c.433G>C	p.Ala145Pro	missense	Exon 5 of 17	ENSP00000621891.1

Frequencies

GnomAD3 genomes AF: 0.0966 AC: 14687 AN: 152072 Hom.: 1259 Cov.: 32

Gnomad AFR AF: 0.0582

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.0935

Gnomad FIN AF: 0.0694

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0711

Gnomad OTH AF: 0.107

GnomAD2 exomes AF: 0.143 AC: 35899 AN: 250206 AF XY: 0.130

Gnomad AFR exome AF: 0.0551

Gnomad AMR exome AF: 0.448

Gnomad ASJ exome AF: 0.0979

Gnomad EAS exome AF: 0.311

Gnomad FIN exome AF: 0.0697

Gnomad NFE exome AF: 0.0718

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.0895 AC: 130642 AN: 1458980 Hom.: 10739 Cov.: 31 AF XY: 0.0882 AC XY: 64058 AN XY: 725914

African (AFR) AF: 0.0574 AC: 1920 AN: 33424

American (AMR) AF: 0.427 AC: 19032 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2746 AN: 26088

East Asian (EAS) AF: 0.342 AC: 13513 AN: 39504

South Asian (SAS) AF: 0.0855 AC: 7368 AN: 86152

European-Finnish (FIN) AF: 0.0650 AC: 3428 AN: 52704

Middle Eastern (MID) AF: 0.0916 AC: 527 AN: 5756

European-Non Finnish (NFE) AF: 0.0687 AC: 76301 AN: 1110496

Other (OTH) AF: 0.0963 AC: 5807 AN: 60304

GnomAD4 genome AF: 0.0967 AC: 14720 AN: 152190 Hom.: 1272 Cov.: 32 AF XY: 0.100 AC XY: 7476 AN XY: 74406

African (AFR) AF: 0.0583 AC: 2420 AN: 41524

American (AMR) AF: 0.264 AC: 4028 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 349 AN: 3468

East Asian (EAS) AF: 0.313 AC: 1616 AN: 5162

South Asian (SAS) AF: 0.0928 AC: 448 AN: 4830

European-Finnish (FIN) AF: 0.0694 AC: 735 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0711 AC: 4832 AN: 68008

Other (OTH) AF: 0.113 AC: 238 AN: 2112

Alfa AF: 0.0873 Hom.: 731

Bravo AF: 0.115

TwinsUK AF: 0.0707 AC: 262

ALSPAC AF: 0.0739 AC: 285

ESP6500AA AF: 0.0592 AC: 261

ESP6500EA AF: 0.0731 AC: 629

ExAC AF: 0.130 AC: 15807

Asia WGS AF: 0.247 AC: 860 AN: 3476

EpiCase AF: 0.0733

EpiControl AF: 0.0755

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.0
DANN	Benign	0.94
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.00059	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.18
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.041
Sift	Benign	0.36	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.036
MPC		0.19
ClinPred		0.0010	T
GERP RS		0.78
Varity_R		0.041
gMVP		0.19
Mutation Taster		=95/5	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: rs2070150; hg19: chr1-161761276; COSMIC: COSV63405837;