6-32117917-C-T

Position:

• chr6-32117917-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_004381.5(ATF6B):​c.1366G>A​(p.Gly456Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: ATF6B NM_004381.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.25

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046700478).
• BP6: Variant 6-32117917-C-T is Benign according to our data. Variant chr6-32117917-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3442466.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.1366G>A	p.Gly456Arg	missense_variant	12/18	ENST00000375203.8	NP_004372.3
ATF6B	NM_001136153.2	c.1357G>A	p.Gly453Arg	missense_variant	12/18		NP_001129625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATF6B	ENST00000375203.8	c.1366G>A	p.Gly456Arg	missense_variant	12/18	1	NM_004381.5	ENSP00000364349.3
ATF6B	ENST00000375201.8	c.1357G>A	p.Gly453Arg	missense_variant	12/18	1		ENSP00000364347.4
ATF6B	ENST00000453203.2	c.1366G>A	p.Gly456Arg	missense_variant	12/18	5		ENSP00000393419.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Aug 28, 2024

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	0.082
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.74
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.71	.;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.49	N;N;.
REVEL	Benign	0.044
Sift	Benign	0.38	T;T;.
Sift4G	Benign	0.50	T;T;.
Polyphen		0.0010	B;B;.
Vest4		0.037
MutPred		0.10		Loss of glycosylation at S457 (P = 0.0922);.;Loss of glycosylation at S457 (P = 0.0922);
MVP		0.53
MPC		0.55
ClinPred		0.091	T
GERP RS		4.1
Varity_R		0.065
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-32085694;