1-161791522-C-T

Variant names:

• chr1-161791522-C-T
• rs1135983
• NM_007348.4:c.469C>T

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.469C>T​(p.Pro157Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0939 in 1,607,720 control chromosomes in the GnomAD database, including 12,636 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1613 hom., cov: 32)
  • Exomes 𝑓: 0.091 (11023 hom.)
• Consequence: ATF6 NM_007348.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.453
• Publications: 27 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=0.002713263).
• BP6: Variant 1-161791522-C-T is Benign according to our data. Variant chr1-161791522-C-T is described in ClinVar as Benign. ClinVar VariationId is 1164407.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.469C>T	p.Pro157Ser	missense	Exon 5 of 16	NP_031374.2	P18850
	ATF6	NM_001437597.1		c.469C>T	p.Pro157Ser	missense	Exon 5 of 16	NP_001424526.1	A0A7P0Z421
	ATF6	NM_001410890.1		c.469C>T	p.Pro157Ser	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.469C>T	p.Pro157Ser	missense	Exon 5 of 16	ENSP00000356919.3	P18850
	ATF6	ENST00000681492.1		c.469C>T	p.Pro157Ser	missense	Exon 5 of 17	ENSP00000506139.1	A0A7P0TAH1
	ATF6	ENST00000951832.1		c.469C>T	p.Pro157Ser	missense	Exon 5 of 17	ENSP00000621891.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 18003 AN: 151992 Hom.: 1598 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.0940

Gnomad FIN AF: 0.0692

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0712

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.149 AC: 36827 AN: 247808 AF XY: 0.133

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.450

Gnomad ASJ exome AF: 0.0973

Gnomad EAS exome AF: 0.310

Gnomad FIN exome AF: 0.0690

Gnomad NFE exome AF: 0.0718

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.0913 AC: 132966 AN: 1455610 Hom.: 11023 Cov.: 31 AF XY: 0.0897 AC XY: 64986 AN XY: 724352

African (AFR) AF: 0.133 AC: 4430 AN: 33288

American (AMR) AF: 0.429 AC: 18934 AN: 44104

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2723 AN: 25998

East Asian (EAS) AF: 0.342 AC: 13458 AN: 39392

South Asian (SAS) AF: 0.0855 AC: 7353 AN: 85958

European-Finnish (FIN) AF: 0.0650 AC: 3347 AN: 51522

Middle Eastern (MID) AF: 0.0957 AC: 551 AN: 5758

European-Non Finnish (NFE) AF: 0.0685 AC: 76039 AN: 1109390

Other (OTH) AF: 0.102 AC: 6131 AN: 60200

GnomAD4 genome AF: 0.119 AC: 18047 AN: 152110 Hom.: 1613 Cov.: 32 AF XY: 0.122 AC XY: 9047 AN XY: 74370

African (AFR) AF: 0.136 AC: 5623 AN: 41464

American (AMR) AF: 0.269 AC: 4110 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 352 AN: 3472

East Asian (EAS) AF: 0.313 AC: 1616 AN: 5160

South Asian (SAS) AF: 0.0933 AC: 450 AN: 4824

European-Finnish (FIN) AF: 0.0692 AC: 733 AN: 10588

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

European-Non Finnish (NFE) AF: 0.0712 AC: 4841 AN: 68008

Other (OTH) AF: 0.127 AC: 268 AN: 2112

Alfa AF: 0.100 Hom.: 2659

Bravo AF: 0.140

TwinsUK AF: 0.0707 AC: 262

ALSPAC AF: 0.0739 AC: 285

ESP6500AA AF: 0.130 AC: 573

ESP6500EA AF: 0.0736 AC: 633

ExAC AF: 0.137 AC: 16680

Asia WGS AF: 0.255 AC: 888 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	0.075
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.45
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.059
Sift	Benign	0.21	T
Sift4G	Benign	0.65	T
Polyphen		0.031	B
Vest4		0.039
MPC		0.15
ClinPred		0.0019	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.028
gMVP		0.30
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1135983; hg19: chr1-161761312; COSMIC: COSV63406311;