1-161781951-A-G

Position:

• chr1-161781951-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000367942.4(ATF6):​c.199A>G​(p.Met67Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 1,606,008 control chromosomes in the GnomAD database, including 61,518 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. M67L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (4127 hom., cov: 32)
  • Exomes 𝑓: 0.27 (57391 hom.)
• Consequence: ATF6 ENST00000367942.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.56

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014133751).
• BP6: Variant 1-161781951-A-G is Benign according to our data. Variant chr1-161781951-A-G is described in ClinVar as [Benign]. Clinvar id is 801568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATF6	NM_007348.4	c.199A>G	p.Met67Val	missense_variant	3/16	ENST00000367942.4	NP_031374.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATF6	ENST00000367942.4	c.199A>G	p.Met67Val	missense_variant	3/16	1	NM_007348.4	ENSP00000356919	A2

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31710 AN: 152082 Hom.: 4129 Cov.: 32

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.234 AC: 58115 AN: 248664 Hom.: 7545 AF XY: 0.237 AC XY: 31843 AN XY: 134504

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.282

Gnomad SAS exome AF: 0.164

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.274 AC: 397833 AN: 1453808 Hom.: 57391 Cov.: 30 AF XY: 0.271 AC XY: 196369 AN XY: 723558

Gnomad4 AFR exome AF: 0.0415

Gnomad4 AMR exome AF: 0.162

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.307

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.294

Gnomad4 NFE exome AF: 0.293

Gnomad4 OTH exome AF: 0.258

GnomAD4 genome AF: 0.208 AC: 31703 AN: 152200 Hom.: 4127 Cov.: 32 AF XY: 0.208 AC XY: 15512 AN XY: 74404

Gnomad4 AFR AF: 0.0514

Gnomad4 AMR AF: 0.199

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.277

Gnomad4 SAS AF: 0.165

Gnomad4 FIN AF: 0.304

Gnomad4 NFE AF: 0.286

Gnomad4 OTH AF: 0.216

Alfa AF: 0.265 Hom.: 11632

Bravo AF: 0.196

TwinsUK AF: 0.297 AC: 1102

ALSPAC AF: 0.290 AC: 1119

ESP6500AA AF: 0.0567 AC: 250

ESP6500EA AF: 0.291 AC: 2505

ExAC AF: 0.234 AC: 28470

Asia WGS AF: 0.201 AC: 698 AN: 3476

EpiCase AF: 0.292

EpiControl AF: 0.282

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Achromatopsia 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.024
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.035	P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.13
Sift	Benign	0.37	T
Sift4G	Benign	0.23	T
Polyphen		0.049	B
Vest4		0.22
MPC		0.15
ClinPred		0.016	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.076

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

Publications

LitVar

Other links and lift over

dbSNP: rs1058405; hg19: chr1-161751741; COSMIC: COSV63406746;