5-173091051-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_153607.3(CREBRF):​c.872C>T​(p.Pro291Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,614,048 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: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

CREBRF
NM_153607.3 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.54
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.06302068).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CREBRFNM_153607.3 linkc.872C>T p.Pro291Leu missense_variant Exon 4 of 9 ENST00000296953.6 NP_705835.2 Q8IUR6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CREBRFENST00000296953.6 linkc.872C>T p.Pro291Leu missense_variant Exon 4 of 9 1 NM_153607.3 ENSP00000296953.2 Q8IUR6-1
CREBRFENST00000520420.5 linkc.872C>T p.Pro291Leu missense_variant Exon 4 of 4 1 ENSP00000428290.1 Q8IUR6-2
CREBRFENST00000522692.5 linkc.872C>T p.Pro291Leu missense_variant Exon 4 of 4 1 ENSP00000431107.1 Q8IUR6-2
CREBRFENST00000520464.1 linkn.1149C>T non_coding_transcript_exon_variant Exon 4 of 7 2

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152166
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000235
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000287
AC:
72
AN:
251120
Hom.:
0
AF XY:
0.000206
AC XY:
28
AN XY:
135726
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000810
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:
0.000388
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000394
AC:
576
AN:
1461882
Hom.:
0
Cov.:
32
AF XY:
0.000360
AC XY:
262
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.000480
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152166
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000235
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000458
Hom.:
0
Bravo
AF:
0.000246
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000698
AC:
6
ExAC
AF:
0.000305
AC:
37
EpiCase
AF:
0.000382
EpiControl
AF:
0.000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 20, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.872C>T (p.P291L) alteration is located in exon 4 (coding exon 3) of the CREBRF gene. This alteration results from a C to T substitution at nucleotide position 872, causing the proline (P) at amino acid position 291 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
Benign
0.15
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.038
.;T;.
Eigen
Benign
0.091
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.95
.;D;D
M_CAP
Benign
0.0092
T
MetaRNN
Benign
0.063
T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
2.0
M;M;M
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-5.6
D;N;D
REVEL
Benign
0.27
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.024
D;T;D
Polyphen
0.70
P;B;P
Vest4
0.55
MVP
0.043
MPC
0.26
ClinPred
0.56
D
GERP RS
5.4
Varity_R
0.36
gMVP
0.30

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.

Other links and lift over

dbSNP: rs150982426; hg19: chr5-172518054; COSMIC: COSV51635449; COSMIC: COSV51635449; API