11-85664254-T-C

Variant summary

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

The NM_001039618.4(CREBZF):c.622A>G(p.Lys208Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,590 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: 6.8e-7 (0 hom.)
• Consequence: CREBZF NM_001039618.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

Genes affected

CREBZF (HGNC:24905): (CREB/ATF bZIP transcription factor) Enables identical protein binding activity. Involved in negative regulation of gene expression, epigenetic; regulation of transcription, DNA-templated; and response to virus. Located in mitochondrion and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.25243554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBZF	NM_001039618.4	c.622A>G	p.Lys208Glu	missense_variant	1/1	ENST00000527447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBZF	ENST00000527447.2	c.622A>G	p.Lys208Glu	missense_variant	1/1		NM_001039618.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460590 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726616

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: 8.99e-7

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

Jan 02, 2024

The c.622A>G (p.K208E) alteration is located in exon 1 (coding exon 1) of the CREBZF gene. This alteration results from a A to G substitution at nucleotide position 622, causing the lysine (K) at amino acid position 208 to be replaced by a glutamic acid (E). 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	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	0.58	D;D;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.12
Sift	Benign	0.26	T
Sift4G	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.20
MutPred		0.18		Loss of MoRF binding (P = 0.0028);
MVP		0.15
MPC		1.9
ClinPred		0.89	D
GERP RS		4.9
Varity_R		0.14
gMVP		0.62

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: chr11-85375298;