1-161766419-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_007348.4(ATF6):c.59T>C(p.Phe20Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,613,306 control chromosomes in the GnomAD database, including 247 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (8 hom., cov: 32)
  • Exomes 𝑓: 0.016 (239 hom.)
• Consequence: ATF6 NM_007348.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.08

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]

LOC124904444 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039719343).
• BP6: Variant 1-161766419-T-C is Benign according to our data. Variant chr1-161766419-T-C is described in ClinVar as [Benign]. Clinvar id is 1170814.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.01 (1528/152276) while in subpopulation SAS AF= 0.0174 (84/4824). AF 95% confidence interval is 0.0157. There are 8 homozygotes in gnomad4. There are 692 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATF6	NM_007348.4	c.59T>C	p.Phe20Ser	missense_variant	1/16	ENST00000367942.4
LOC124904444	XR_007066695.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATF6	ENST00000367942.4	c.59T>C	p.Phe20Ser	missense_variant	1/16	1	NM_007348.4	A2

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1526 AN: 152158 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.0113 AC: 2843 AN: 250562 Hom.: 22 AF XY: 0.0122 AC XY: 1656 AN XY: 135450

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00540

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0175

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0162 AC: 23735 AN: 1461030 Hom.: 239 Cov.: 31 AF XY: 0.0163 AC XY: 11864 AN XY: 726802

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00568

Gnomad4 ASJ exome AF: 0.00452

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0189

Gnomad4 FIN exome AF: 0.00341

Gnomad4 NFE exome AF: 0.0184

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome AF: 0.0100 AC: 1528 AN: 152276 Hom.: 8 Cov.: 32 AF XY: 0.00929 AC XY: 692 AN XY: 74462

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.0150 Hom.: 38

Bravo AF: 0.00953

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0169 AC: 65

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0167 AC: 144

ExAC AF: 0.0122 AC: 1478

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0155

EpiControl AF: 0.0172

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	15
Dann	Benign	0.72
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00057	N
LIST_S2	Benign	0.091	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.81	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.020
Sift	Benign	0.75	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.081
MPC		0.26
ClinPred		0.0019	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.067

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

Publications

LitVar

Other links and lift over

dbSNP: rs35284289; hg19: chr1-161736209;