chr1-161781910-A-AG

Variant names:

• chr1-161781910-A-AG
• rs1553227755
• NM_007348.4:c.160dupG

Variant summary

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

The ENST00000367942.4(ATF6):​c.160-2_160-1insG variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000138 in 1,445,762 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATF6 ENST00000367942.4 splice_acceptor, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.54
• 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 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.5, offset of -1, new splice context is: tgctgatttgaaacctacAGgga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-161781910-A-AG is Pathogenic according to our data. Variant chr1-161781910-A-AG is described in ClinVar as Pathogenic. ClinVar VariationId is 505015.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367942.4. 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.160dupG	p.Glu54fs	frameshift splice_region	Exon 3 of 16	NP_031374.2	P18850
	ATF6	NM_001437597.1		c.160dupG	p.Glu54fs	frameshift splice_region	Exon 3 of 16	NP_001424526.1	A0A7P0Z421
	ATF6	NM_001410890.1		c.160dupG	p.Glu54fs	frameshift splice_region	Exon 3 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.160-2_160-1insG		splice_acceptor intron	N/A	ENSP00000356919.3	P18850
	ATF6	ENST00000681492.1		c.160-2_160-1insG		splice_acceptor intron	N/A	ENSP00000506139.1	A0A7P0TAH1
	ATF6	ENST00000951832.1		c.160-2_160-1insG		splice_acceptor intron	N/A	ENSP00000621891.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445762 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 719490

African (AFR) AF: 0.00 AC: 0 AN: 33102

American (AMR) AF: 0.00 AC: 0 AN: 42612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39460

South Asian (SAS) AF: 0.00 AC: 0 AN: 84072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102010

Other (OTH) AF: 0.00 AC: 0 AN: 59854

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Achromatopsia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 1
DS_AL_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553227755; hg19: chr1-161751700;