1-161770693-G-T

Variant names:

• chr1-161770693-G-T
• rs4657103
• NM_007348.4:c.82+4251G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007348.4(ATF6):​c.82+4251G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.899 in 152,296 control chromosomes in the GnomAD database, including 61,695 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.90 (61695 hom., cov: 33)
• Consequence: ATF6 NM_007348.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.834
• 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

LOC124904444 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

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.82+4251G>T		intron	N/A	NP_031374.2
	ATF6	NM_001437597.1		c.82+4251G>T		intron	N/A	NP_001424526.1
	ATF6	NM_001410890.1		c.82+4251G>T		intron	N/A	NP_001397819.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6	ENST00000367942.4	TSL:1 MANE Select	c.82+4251G>T		intron	N/A	ENSP00000356919.3
	ATF6	ENST00000681492.1		c.82+4251G>T		intron	N/A	ENSP00000506139.1
	ATF6	ENST00000680688.1		c.82+4251G>T		intron	N/A	ENSP00000504865.1

Frequencies

GnomAD3 genomes AF: 0.899 AC: 136765 AN: 152178 Hom.: 61631 Cov.: 33

Gnomad AFR AF: 0.960

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.888

Gnomad ASJ AF: 0.888

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.906

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.871

Gnomad OTH AF: 0.901

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.899 AC: 136889 AN: 152296 Hom.: 61695 Cov.: 33 AF XY: 0.898 AC XY: 66868 AN XY: 74470

African (AFR) AF: 0.960 AC: 39914 AN: 41572

American (AMR) AF: 0.888 AC: 13586 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.888 AC: 3083 AN: 3470

East Asian (EAS) AF: 0.883 AC: 4576 AN: 5184

South Asian (SAS) AF: 0.835 AC: 4031 AN: 4826

European-Finnish (FIN) AF: 0.906 AC: 9610 AN: 10602

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.871 AC: 59272 AN: 68024

Other (OTH) AF: 0.902 AC: 1906 AN: 2112

Alfa AF: 0.886 Hom.: 12431

Bravo AF: 0.902

Asia WGS AF: 0.892 AC: 3104 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.3
DANN	Benign	0.64
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

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: rs4657103; hg19: chr1-161740483;