5-173090678-C-A

Variant names:

• chr5-173090678-C-A
• rs932504156
• NM_153607.3:c.499C>A

Variant summary

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

The NM_153607.3(CREBRF):​c.499C>A​(p.Pro167Thr) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P167L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREBRF NM_153607.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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]

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=0.103066385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBRF	NM_153607.3	c.499C>A	p.Pro167Thr	missense_variant	Exon 4 of 9	ENST00000296953.6	NP_705835.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBRF	ENST00000296953.6	c.499C>A	p.Pro167Thr	missense_variant	Exon 4 of 9	1	NM_153607.3	ENSP00000296953.2
CREBRF	ENST00000520420.5	c.499C>A	p.Pro167Thr	missense_variant	Exon 4 of 4	1		ENSP00000428290.1
CREBRF	ENST00000522692.5	c.499C>A	p.Pro167Thr	missense_variant	Exon 4 of 4	1		ENSP00000431107.1
CREBRF	ENST00000520464.1	n.776C>A		non_coding_transcript_exon_variant	Exon 4 of 7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.499C>A (p.P167T) 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 499, causing the proline (P) at amino acid position 167 to be replaced by a threonine (T). 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	0.061
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	.;T;.
Eigen	Benign	0.076
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.69	N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D;N;D
REVEL	Benign	0.19
Sift	Benign	0.072	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.56	P;B;P
Vest4		0.17
MutPred		0.17		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.043
MPC		0.36
ClinPred		0.69	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.21

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

Other links and lift over

dbSNP: rs932504156; hg19: chr5-172517681;