1-161766385-G-A

Variant names:

• chr1-161766385-G-A
• rs1684260978
• NM_007348.4:c.25G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007348.4(ATF6):​c.25G>A​(p.Gly9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G9G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ATF6 NM_007348.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.519
• Publications: 0 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-DT (HGNC:55826): (ATF6 divergent transcript)

LOC124904444 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18975547).

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.25G>A	p.Gly9Ser	missense	Exon 1 of 16	NP_031374.2	P18850
	ATF6	NM_001437597.1		c.25G>A	p.Gly9Ser	missense	Exon 1 of 16	NP_001424526.1	A0A7P0Z421
	ATF6	NM_001410890.1		c.25G>A	p.Gly9Ser	missense	Exon 1 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.25G>A	p.Gly9Ser	missense	Exon 1 of 16	ENSP00000356919.3	P18850
	ATF6	ENST00000681492.1		c.25G>A	p.Gly9Ser	missense	Exon 1 of 17	ENSP00000506139.1	A0A7P0TAH1
	ATF6	ENST00000951832.1		c.25G>A	p.Gly9Ser	missense	Exon 1 of 17	ENSP00000621891.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460618 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726594

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111388

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.52
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.021
Sift	Benign	0.044	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.57	P
Vest4		0.37
MutPred		0.35		Gain of glycosylation at G9 (P = 0.01)
MVP		0.39
MPC		0.14
ClinPred		0.50	T
GERP RS		2.6
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.092
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1684260978; hg19: chr1-161736175;