rs2499855

Variant names:

• chr1-161959971-C-T
• rs2499855
• NM_007348.4:c.*1317C>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.*1317C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.902 in 152,240 control chromosomes in the GnomAD database, including 62,117 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 (62117 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: ATF6 NM_007348.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.916
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATF6	NM_007348.4	c.*1317C>T		3_prime_UTR_variant	Exon 16 of 16	ENST00000367942.4	NP_031374.2
ATF6	NM_001437597.1	c.*1317C>T		3_prime_UTR_variant	Exon 16 of 16		NP_001424526.1
ATF6	NM_001410890.1	c.*1317C>T		3_prime_UTR_variant	Exon 16 of 16		NP_001397819.1
ATF6	XM_011509309.1	c.*1317C>T		3_prime_UTR_variant	Exon 16 of 16		XP_011507611.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATF6	ENST00000367942.4	c.*1317C>T		3_prime_UTR_variant	Exon 16 of 16	1	NM_007348.4	ENSP00000356919.3
ATF6	ENST00000679853.1	c.*1317C>T		3_prime_UTR_variant	Exon 16 of 16			ENSP00000506149.1
ATF6	ENST00000681738.1	n.*56+1261C>T		intron_variant	Intron 16 of 16			ENSP00000505025.1
ATF6	ENST00000681801.1	n.*56+1261C>T		intron_variant	Intron 16 of 16			ENSP00000505998.1

Frequencies

GnomAD3 genomes AF: 0.902 AC: 137231 AN: 152122 Hom.: 62054 Cov.: 31

Gnomad AFR AF: 0.961

Gnomad AMI AF: 0.713

Gnomad AMR AF: 0.891

Gnomad ASJ AF: 0.887

Gnomad EAS AF: 0.884

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.908

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.903

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.902 AC: 137354 AN: 152240 Hom.: 62117 Cov.: 31 AF XY: 0.902 AC XY: 67104 AN XY: 74434

African (AFR) AF: 0.961 AC: 39923 AN: 41546

American (AMR) AF: 0.891 AC: 13635 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.887 AC: 3076 AN: 3468

East Asian (EAS) AF: 0.883 AC: 4574 AN: 5178

South Asian (SAS) AF: 0.856 AC: 4135 AN: 4828

European-Finnish (FIN) AF: 0.908 AC: 9620 AN: 10600

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

European-Non Finnish (NFE) AF: 0.876 AC: 59568 AN: 68004

Other (OTH) AF: 0.903 AC: 1910 AN: 2114

Alfa AF: 0.880 Hom.: 25206

Bravo AF: 0.904

Asia WGS AF: 0.895 AC: 3113 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.70
DANN	Benign	0.47
PhyloP100		-0.92
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: rs2499855; hg19: chr1-161929761;