rs797045174

Variant names:

• chr1-161821081-T-TA
• rs797045174
• NM_007348.4:c.1110dupA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_007348.4(ATF6):​c.1110dupA​(p.Val371SerfsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V371V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATF6 NM_007348.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.86
• Publications: 3 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: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• ATF6-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• achromatopsia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-161821081-T-TA is Pathogenic according to our data. Variant chr1-161821081-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 209101.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6	NM_007348.4	MANE Select	c.1110dupA	p.Val371SerfsTer3	frameshift	Exon 9 of 16	NP_031374.2
	ATF6	NM_001437597.1		c.1110dupA	p.Val371SerfsTer3	frameshift	Exon 9 of 16	NP_001424526.1
	ATF6	NM_001410890.1		c.1110dupA	p.Val371SerfsTer3	frameshift	Exon 9 of 16	NP_001397819.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6	ENST00000367942.4	TSL:1 MANE Select	c.1110dupA	p.Val371SerfsTer3	frameshift	Exon 9 of 16	ENSP00000356919.3
	ATF6	ENST00000681492.1		c.1110dupA	p.Val371SerfsTer3	frameshift	Exon 9 of 17	ENSP00000506139.1
	ATF6	ENST00000680688.1		c.1110dupA	p.Val371SerfsTer3	frameshift	Exon 9 of 16	ENSP00000504865.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Achromatopsia 7 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9
Mutation Taster		=9/191	disease causing (ClinVar)

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: rs797045174; hg19: chr1-161790871;