6-32119871-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004381.5(ATF6B):c.919A>C(p.Ile307Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ATF6B NM_004381.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19006065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATF6B	NM_004381.5	c.919A>C	p.Ile307Leu	missense_variant	9/18	ENST00000375203.8
ATF6B	NM_001136153.2	c.910A>C	p.Ile304Leu	missense_variant	9/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATF6B	ENST00000375203.8	c.919A>C	p.Ile307Leu	missense_variant	9/18	1	NM_004381.5	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461870 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.919A>C (p.I307L) alteration is located in exon 9 (coding exon 9) of the ATF6B gene. This alteration results from a A to C substitution at nucleotide position 919, causing the isoleucine (I) at amino acid position 307 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.35	T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.0098
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	0.85	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.89	N;N;.
REVEL	Benign	0.093
Sift	Benign	0.13	T;T;.
Sift4G	Benign	0.20	T;T;.
Polyphen		0.13	B;B;.
Vest4		0.49
MutPred		0.39		Loss of catalytic residue at P309 (P = 0.0307);.;Loss of catalytic residue at P309 (P = 0.0307);
MVP		0.52
MPC		1.3
ClinPred		0.78	D
GERP RS		5.0
Varity_R		0.099
gMVP		0.35

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: chr6-32087648;