1-161766363-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_007348.4(ATF6):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATF6 NM_007348.4 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0510

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-161766363-G-T is Pathogenic according to our data. Variant chr1-161766363-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 977965.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATF6	NM_007348.4	c.3G>T	p.Met1?	start_lost	1/16	ENST00000367942.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATF6	ENST00000367942.4	c.3G>T	p.Met1?	start_lost	1/16	1	NM_007348.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Achromatopsia 7 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Genetics in Ophthalmology, Institut Imagine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.63
Cadd	Benign	2.4
Dann	Benign	0.79
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0037	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.10
Sift	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.1839);
MVP		0.37
ClinPred		0.67	D
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.23

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: rs915211840; hg19: chr1-161736153;