chr6-32117886-G-A

Position:

• chr6-32117886-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004381.5(ATF6B):​c.1397C>T​(p.Pro466Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,423,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATF6B NM_004381.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.22

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13476449).
• BP6: Variant 6-32117886-G-A is Benign according to our data. Variant chr6-32117886-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2269883.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATF6B	NM_004381.5	c.1397C>T	p.Pro466Leu	missense_variant	12/18	ENST00000375203.8	NP_004372.3
ATF6B	NM_001136153.2	c.1388C>T	p.Pro463Leu	missense_variant	12/18		NP_001129625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATF6B	ENST00000375203.8	c.1397C>T	p.Pro466Leu	missense_variant	12/18	1	NM_004381.5	ENSP00000364349	A2
ATF6B	ENST00000375201.8	c.1388C>T	p.Pro463Leu	missense_variant	12/18	1		ENSP00000364347	P4
ATF6B	ENST00000453203.2	c.1397C>T	p.Pro466Leu	missense_variant	12/18	5		ENSP00000393419

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1423220 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 705498

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000520

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.71	.;.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N;N;.
REVEL	Benign	0.085
Sift	Benign	0.036	D;D;.
Sift4G	Benign	0.32	T;T;.
Polyphen		0.27	B;P;.
Vest4		0.12
MutPred		0.16		Loss of glycosylation at P466 (P = 0.0123);.;Loss of glycosylation at P466 (P = 0.0123);
MVP		0.64
MPC		0.47
ClinPred		0.36	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs773465509; hg19: chr6-32085663;