6-32115523-A-G

Variant names:

• chr6-32115523-A-G
• rs8283
• NM_004381.5:c.*216T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004381.5(ATF6B):​c.*216T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 448,564 control chromosomes in the GnomAD database, including 13,151 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 0.26 (5847 hom., cov: 31)
  • Exomes 𝑓: 0.21 (7304 hom.)
• Consequence: ATF6B NM_004381.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.254
• Publications: 38 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.456 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6B	NM_004381.5	MANE Select	c.*216T>C		3_prime_UTR	Exon 18 of 18	NP_004372.3
	ATF6B	NM_001136153.2		c.*216T>C		3_prime_UTR	Exon 18 of 18	NP_001129625.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATF6B	ENST00000375203.8	TSL:1 MANE Select	c.*216T>C		3_prime_UTR	Exon 18 of 18	ENSP00000364349.3
	ATF6B	ENST00000375201.8	TSL:1	c.*216T>C		3_prime_UTR	Exon 18 of 18	ENSP00000364347.4
	ATF6B	ENST00000453203.2	TSL:5	c.*467T>C		3_prime_UTR	Exon 18 of 18	ENSP00000393419.2

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38977 AN: 151898 Hom.: 5844 Cov.: 31

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.282

GnomAD4 exome AF: 0.206 AC: 60980 AN: 296548 Hom.: 7304 Cov.: 3 AF XY: 0.208 AC XY: 31412 AN XY: 151122

African (AFR) AF: 0.386 AC: 3246 AN: 8402

American (AMR) AF: 0.183 AC: 1721 AN: 9384

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 2152 AN: 10412

East Asian (EAS) AF: 0.275 AC: 6731 AN: 24486

South Asian (SAS) AF: 0.450 AC: 4138 AN: 9204

European-Finnish (FIN) AF: 0.141 AC: 3472 AN: 24578

Middle Eastern (MID) AF: 0.301 AC: 449 AN: 1494

European-Non Finnish (NFE) AF: 0.184 AC: 34892 AN: 189456

Other (OTH) AF: 0.218 AC: 4179 AN: 19132

GnomAD4 genome AF: 0.257 AC: 39011 AN: 152016 Hom.: 5847 Cov.: 31 AF XY: 0.260 AC XY: 19310 AN XY: 74344

African (AFR) AF: 0.395 AC: 16369 AN: 41392

American (AMR) AF: 0.200 AC: 3054 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 718 AN: 3470

East Asian (EAS) AF: 0.342 AC: 1764 AN: 5162

South Asian (SAS) AF: 0.472 AC: 2272 AN: 4814

European-Finnish (FIN) AF: 0.136 AC: 1437 AN: 10592

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12549 AN: 67996

Other (OTH) AF: 0.279 AC: 588 AN: 2104

Alfa AF: 0.209 Hom.: 13999

Bravo AF: 0.264

Asia WGS AF: 0.387 AC: 1346 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.6
DANN	Benign	0.83
PhyloP100		0.25
PromoterAI		-0.053	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8283; hg19: chr6-32083300;