NM_007348.4:c.970C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_007348.4(ATF6):c.970C>T(p.Arg324Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,612,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

ATF6
NM_007348.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 2.99

Publications

16 publications found

Variant links:

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

ATF6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.96

PP5

Variant 1-161819693-C-T is Pathogenic according to our data. Variant chr1-161819693-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 208172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATF6	NM_007348.4	MANE Select	c.970C>T	p.Arg324Cys	missense	Exon 8 of 16	NP_031374.2	P18850
ATF6	NM_001437597.1		c.970C>T	p.Arg324Cys	missense	Exon 8 of 16	NP_001424526.1	A0A7P0Z421
ATF6	NM_001410890.1		c.970C>T	p.Arg324Cys	missense	Exon 8 of 16	NP_001397819.1	A0A7P0TAF2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATF6	ENST00000367942.4	TSL:1 MANE Select	c.970C>T	p.Arg324Cys	missense	Exon 8 of 16	ENSP00000356919.3	P18850
ATF6	ENST00000681492.1		c.970C>T	p.Arg324Cys	missense	Exon 8 of 17	ENSP00000506139.1	A0A7P0TAH1
ATF6	ENST00000951832.1		c.970C>T	p.Arg324Cys	missense	Exon 8 of 17	ENSP00000621891.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

249696

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000637

AC:

AN:

1460156

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

726348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33306

American (AMR)

AF:

0.00

AC:

AN:

44476

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39558

South Asian (SAS)

AF:

0.00

AC:

AN:

85984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000783

AC:

AN:

1111282

Other (OTH)

AF:

0.0000995

AC:

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41376

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68010

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000510

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Achromatopsia 7 (3)

ATF6-related disorder (1)

Bilateral sensorineural hearing impairment (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

PhyloP100

3.0

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-7.1

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MVP

0.99

MPC

0.74

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.70

Mutation Taster

=34/66

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over