Genetic Variant NM_004381.5:c.-260G>A (chr6-32128467-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.-260G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0589 in 152,146 control chromosomes in the GnomAD database, including 400 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 0.059 ( 400 hom., cov: 31)

Consequence

ATF6B
NM_004381.5 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.80

Publications

31 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:

FKBPL (HGNC:13949): (FKBP prolyl isomerase like) The protein encoded by this gene has similarity to the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. The encoded protein is thought to have a potential role in the induced radioresistance. Also it appears to have some involvement in the control of the cell cycle. [provided by RefSeq, Jul 2008]

FKBPL 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 (AMR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
ATF6B	NM_004381.5 link	c.-260G>A	upstream_gene_variant	ENST00000375203.8	NP_004372.3
FKBPL	NM_022110.4 link	c.*264G>A	downstream_gene_variant	ENST00000375156.4	NP_071393.2
ATF6B	NM_001136153.2 link	c.-260G>A	upstream_gene_variant		NP_001129625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATF6B	ENST00000375203.8 link	c.-260G>A		upstream_gene_variant		1	NM_004381.5	ENSP00000364349.3
FKBPL	ENST00000375156.4 link	c.*264G>A		downstream_gene_variant		1	NM_022110.4	ENSP00000364298.3

Frequencies

GnomAD3 genomes

AF:

0.0588

AC:

8940

AN:

152028

Hom.:

400

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.143

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.0964

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.127

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0608

Gnomad OTH

AF:

0.0493

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

GnomAD4 genome

AF:

0.0589

AC:

8957

AN:

152146

Hom.:

400

Cov.:

AF XY:

0.0617

AC XY:

4590

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0126

AC:

521

AN:

41512

American (AMR)

AF:

0.144

AC:

2195

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3472

East Asian (EAS)

AF:

0.0968

AC:

501

AN:

5174

South Asian (SAS)

AF:

0.0172

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.127

AC:

1344

AN:

10568

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0607

AC:

4131

AN:

68000

Other (OTH)

AF:

0.0507

AC:

107

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

412

825

1237

1650

2062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0650

Hom.:

988

Bravo

AF:

0.0598

Asia WGS

AF:

0.0680

AC:

238

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

0.021

(source)

DANN

Benign

0.81

PhyloP100

-2.8

PromoterAI

-0.061

Neutral

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over