Genetic Variant CREBRF:p.Ala269Glu (chr5-173090985-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153607.3(CREBRF):c.806C>A(p.Ala269Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CREBRF
NM_153607.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

Variant links:

Genes affected

CREBRF (HGNC:24050): (CREB3 regulatory factor) Enables DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in several processes, including negative regulation of endoplasmic reticulum unfolded protein response; positive regulation of transport; and regulation of transcription by RNA polymerase II. Located in cytoplasm and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

CREBRF links:

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ACMG classification

Classification made for transcript

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=0.20009434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBRF	NM_153607.3 link	c.806C>A	p.Ala269Glu	missense_variant	Exon 4 of 9	ENST00000296953.6	NP_705835.2	Q8IUR6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CREBRF	ENST00000296953.6 link	c.806C>A	p.Ala269Glu	missense_variant	Exon 4 of 9	1	NM_153607.3	ENSP00000296953.2	Q8IUR6-1
CREBRF	ENST00000520420.5 link	c.806C>A	p.Ala269Glu	missense_variant	Exon 4 of 4	1		ENSP00000428290.1	Q8IUR6-2
CREBRF	ENST00000522692.5 link	c.806C>A	p.Ala269Glu	missense_variant	Exon 4 of 4	1		ENSP00000431107.1	Q8IUR6-2
CREBRF	ENST00000520464.1 link	n.1083C>A		non_coding_transcript_exon_variant	Exon 4 of 7	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251012

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.806C>A (p.A269E) alteration is located in exon 4 (coding exon 3) of the CREBRF gene. This alteration results from a C to A substitution at nucleotide position 806, causing the alanine (A) at amino acid position 269 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

Benign

0.26

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.033

.;T;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.58

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

.;D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L;L

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.2

D;N;D

REVEL

Benign

0.12

Sift

Uncertain

0.0010

D;D;D

Sift4G

Benign

0.37

T;T;T

Polyphen

0.23

B;B;B

Vest4

0.32

MutPred

0.64

Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);

MVP

0.27

MPC

0.33

ClinPred

0.18

GERP RS

1.7

Varity_R

0.13

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over