6-32115398-C-T

Variant names:

• chr6-32115398-C-T
• rs8111
• NM_004381.5:c.*341G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_004381.5(ATF6B):​c.*341G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 136,292 control chromosomes in the GnomAD database, including 5,748 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (4627 hom., cov: 22)
  • Exomes 𝑓: 0.55 (1121 hom.)
• Consequence: ATF6B NM_004381.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15
• Publications: 57 publications found

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]

ENSG00000284829 (HGNC:):

TNXB (HGNC:11976): (tenascin XB) This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing, and its deficiency has been associated with the connective tissue disorder Ehlers-Danlos syndrome. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. It is one of four genes in this cluster which have been duplicated. The duplicated copy of this gene is incomplete and is a pseudogene which is transcribed but does not encode a protein. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TNXB Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome due to tenascin-X deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, PanelApp Australia
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• vesicoureteral reflux 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004381.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6B	NM_004381.5	MANE Select	c.*341G>A		3_prime_UTR	Exon 18 of 18	NP_004372.3
	ATF6B	NM_001136153.2		c.*341G>A		3_prime_UTR	Exon 18 of 18	NP_001129625.1	Q99941-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6B	ENST00000375203.8	TSL:1 MANE Select	c.*341G>A		3_prime_UTR	Exon 18 of 18	ENSP00000364349.3	Q99941-1
	ATF6B	ENST00000375201.8	TSL:1	c.*341G>A		3_prime_UTR	Exon 18 of 18	ENSP00000364347.4	Q99941-2
	ATF6B	ENST00000932422.1		c.*341G>A		3_prime_UTR	Exon 18 of 18	ENSP00000602481.1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 32425 AN: 123342 Hom.: 4623 Cov.: 22

Gnomad AFR AF: 0.0679

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.372

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.275

GnomAD4 exome AF: 0.555 AC: 7150 AN: 12894 Hom.: 1121 Cov.: 0 AF XY: 0.553 AC XY: 3586 AN XY: 6486

African (AFR) AF: 0.359 AC: 56 AN: 156

American (AMR) AF: 0.571 AC: 202 AN: 354

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 515 AN: 820

East Asian (EAS) AF: 0.499 AC: 402 AN: 806

South Asian (SAS) AF: 0.480 AC: 49 AN: 102

European-Finnish (FIN) AF: 0.562 AC: 429 AN: 764

Middle Eastern (MID) AF: 0.578 AC: 52 AN: 90

European-Non Finnish (NFE) AF: 0.556 AC: 4943 AN: 8898

Other (OTH) AF: 0.555 AC: 502 AN: 904

GnomAD4 genome AF: 0.263 AC: 32439 AN: 123398 Hom.: 4627 Cov.: 22 AF XY: 0.271 AC XY: 16017 AN XY: 59104

African (AFR) AF: 0.0678 AC: 2012 AN: 29670

American (AMR) AF: 0.367 AC: 4123 AN: 11234

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1514 AN: 3278

East Asian (EAS) AF: 0.209 AC: 787 AN: 3770

South Asian (SAS) AF: 0.227 AC: 806 AN: 3554

European-Finnish (FIN) AF: 0.480 AC: 3674 AN: 7650

Middle Eastern (MID) AF: 0.379 AC: 91 AN: 240

European-Non Finnish (NFE) AF: 0.303 AC: 18598 AN: 61466

Other (OTH) AF: 0.278 AC: 473 AN: 1702

Alfa AF: 0.263 Hom.: 16773

Bravo AF: 0.210

Asia WGS AF: 0.199 AC: 695 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	16
DANN	Benign	0.93
PhyloP100		2.2
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Mutation Taster		=96/4	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: rs8111; hg19: chr6-32083175;