1-161791522-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007348.4(ATF6):​c.469C>G​(p.Pro157Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P157S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATF6 NM_007348.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045456976).

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>G	p.Pro157Ala	missense	Exon 5 of 16	NP_031374.2	P18850
	ATF6	NM_001437597.1		c.469C>G	p.Pro157Ala	missense	Exon 5 of 16	NP_001424526.1	A0A7P0Z421
	ATF6	NM_001410890.1		c.469C>G	p.Pro157Ala	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>G	p.Pro157Ala	missense	Exon 5 of 16	ENSP00000356919.3	P18850
	ATF6	ENST00000681492.1		c.469C>G	p.Pro157Ala	missense	Exon 5 of 17	ENSP00000506139.1	A0A7P0TAH1
	ATF6	ENST00000951832.1		c.469C>G	p.Pro157Ala	missense	Exon 5 of 17	ENSP00000621891.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.75
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.45
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.043
Sift	Benign	0.22	T
Sift4G	Benign	0.70	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.15		Gain of MoRF binding (P = 0.0466)
MVP		0.23
MPC		0.14
ClinPred		0.041	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.26
Mutation Taster		=88/12	polymorphism

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;