6-32116560-T-A

Position:

• chr6-32116560-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004381.5(ATF6B):​c.1802A>T​(p.His601Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00501 in 1,597,248 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (53 hom.)
• Consequence: ATF6B NM_004381.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.88

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027816862).
• BP6: Variant 6-32116560-T-A is Benign according to our data. Variant chr6-32116560-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 771155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATF6B	NM_004381.5	c.1802A>T	p.His601Leu	missense_variant	17/18	ENST00000375203.8	NP_004372.3
ATF6B	NM_001136153.2	c.1793A>T	p.His598Leu	missense_variant	17/18		NP_001129625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATF6B	ENST00000375203.8	c.1802A>T	p.His601Leu	missense_variant	17/18	1	NM_004381.5	ENSP00000364349	A2
ATF6B	ENST00000375201.8	c.1793A>T	p.His598Leu	missense_variant	17/18	1		ENSP00000364347	P4
ATF6B	ENST00000453203.2	c.1825A>T	p.Thr609Ser	missense_variant	17/18	5		ENSP00000393419

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 651 AN: 151986 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00793

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00513 AC: 1216 AN: 236924 Hom.: 13 AF XY: 0.00556 AC XY: 706 AN XY: 127060

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.00253

Gnomad ASJ exome AF: 0.00272

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.000624

Gnomad FIN exome AF: 0.00133

Gnomad NFE exome AF: 0.00952

Gnomad OTH exome AF: 0.00628

GnomAD4 exome AF: 0.00508 AC: 7345 AN: 1445144 Hom.: 53 Cov.: 32 AF XY: 0.00531 AC XY: 3805 AN XY: 716644

Gnomad4 AFR exome AF: 0.000600

Gnomad4 AMR exome AF: 0.00272

Gnomad4 ASJ exome AF: 0.00303

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.000671

Gnomad4 FIN exome AF: 0.00108

Gnomad4 NFE exome AF: 0.00610

Gnomad4 OTH exome AF: 0.00442

GnomAD4 genome AF: 0.00428 AC: 651 AN: 152104 Hom.: 6 Cov.: 32 AF XY: 0.00381 AC XY: 283 AN XY: 74366

Gnomad4 AFR AF: 0.000603

Gnomad4 AMR AF: 0.00341

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00793

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00611 Hom.: 3

Bravo AF: 0.00448

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00552 AC: 670

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-10	D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.89
MVP		0.88
MPC		1.5
ClinPred		0.091	T
GERP RS		5.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.18
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs147955878; hg19: chr6-32084337; COSMIC: COSV99056436; COSMIC: COSV99056436;