Genetic Variant NM_004381.5:c.1424+38G>A (chr6-32117821-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004381.5(ATF6B):c.1424+38G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,555,400 control chromosomes in the GnomAD database, including 1,570 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 0.049 ( 264 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1306 hom. )

Consequence

ATF6B
NM_004381.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.18

Publications

21 publications found

Variant links:

Genes affected

ATF6B (HGNC:2349): (activating transcription factor 6 beta) The protein encoded by this gene is a transcription factor in the unfolded protein response (UPR) pathway during ER stress. Either as a homodimer or as a heterodimer with ATF6-alpha, the encoded protein binds to the ER stress response element, interacting with nuclear transcription factor Y to activate UPR target genes. The protein is normally found in the membrane of the endoplasmic reticulum; however, under ER stress, the N-terminal cytoplasmic domain is cleaved from the rest of the protein and translocates to the nucleus. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ATF6B links:

ENSG00000284829 (HGNC:):

ENSG00000284829 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATF6B	NM_004381.5 link	c.1424+38G>A		intron_variant	Intron 12 of 17	ENST00000375203.8	NP_004372.3	Q99941-1Q6AZW6
ATF6B	NM_001136153.2 link	c.1415+38G>A		intron_variant	Intron 12 of 17		NP_001129625.1	Q99941-2A0A1U9X796

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATF6B	ENST00000375203.8 link	c.1424+38G>A	intron_variant	Intron 12 of 17	1	NM_004381.5	ENSP00000364349.3	Q99941-1
ATF6B	ENST00000375201.8 link	c.1415+38G>A	intron_variant	Intron 12 of 17	1		ENSP00000364347.4	Q99941-2
ATF6B	ENST00000453203.2 link	c.1424+38G>A	intron_variant	Intron 12 of 17	5		ENSP00000393419.2	H0Y7D7
ENSG00000284829	ENST00000494022.1 link	n.-211G>A	upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0491

AC:

7470

AN:

152068

Hom.:

264

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0971

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.0513

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0360

Gnomad OTH

AF:

0.0507

GnomAD2 exomes

AF:

0.0297

AC:

5218

AN:

175784

AF XY:

0.0273

show subpopulations

Gnomad AFR exome

AF:

0.0974

Gnomad AMR exome

AF:

0.0393

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00378

Gnomad NFE exome

AF:

0.0352

Gnomad OTH exome

AF:

0.0381

GnomAD4 exome

AF:

0.0387

AC:

54328

AN:

1403214

Hom.:

1306

Cov.:

AF XY:

0.0368

AC XY:

25503

AN XY:

692910

show subpopulations

African (AFR)

AF:

0.0949

AC:

3040

AN:

32040

American (AMR)

AF:

0.0404

AC:

1386

AN:

34334

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

339

AN:

22574

East Asian (EAS)

AF:

0.0000513

AC:

AN:

38976

South Asian (SAS)

AF:

0.000416

AC:

AN:

76954

European-Finnish (FIN)

AF:

0.00431

AC:

217

AN:

50392

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

5326

European-Non Finnish (NFE)

AF:

0.0434

AC:

47079

AN:

1084628

Other (OTH)

AF:

0.0376

AC:

2178

AN:

57990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

3158

6316

9475

12633

15791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1936

3872

5808

7744

9680

<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:

0.0491

AC:

7477

AN:

152186

Hom.:

264

Cov.:

AF XY:

0.0464

AC XY:

3453

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0969

AC:

4024

AN:

41506

American (AMR)

AF:

0.0513

AC:

784

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0360

AC:

2451

AN:

68002

Other (OTH)

AF:

0.0501

AC:

106

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

350

700

1050

1400

1750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0375

Hom.:

315

Bravo

AF:

0.0565

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.39

(source)

DANN

Benign

0.76

PhyloP100

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over