5-173090739-C-T

Variant names:

• chr5-173090739-C-T
• rs1255004762
• NM_153607.3:c.560C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153607.3(CREBRF):​c.560C>T​(p.Ser187Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S187C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CREBRF NM_153607.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.91
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• inherited obesity

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28661296).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153607.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBRF	NM_153607.3	MANE Select	c.560C>T	p.Ser187Phe	missense	Exon 4 of 9	NP_705835.2	Q8IUR6-1
	CREBRF	NM_001168393.2		c.560C>T	p.Ser187Phe	missense	Exon 4 of 4	NP_001161865.1	Q8IUR6-2
	CREBRF	NM_001168394.2		c.560C>T	p.Ser187Phe	missense	Exon 4 of 4	NP_001161866.1	Q8IUR6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBRF	ENST00000296953.6	TSL:1 MANE Select	c.560C>T	p.Ser187Phe	missense	Exon 4 of 9	ENSP00000296953.2	Q8IUR6-1
	CREBRF	ENST00000520420.5	TSL:1	c.560C>T	p.Ser187Phe	missense	Exon 4 of 4	ENSP00000428290.1	Q8IUR6-2
	CREBRF	ENST00000522692.5	TSL:1	c.560C>T	p.Ser187Phe	missense	Exon 4 of 4	ENSP00000431107.1	Q8IUR6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.97	L
PhyloP100		4.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.25		Loss of disorder (P = 0.0409)
MVP		0.093
MPC		0.85
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.36
gMVP		0.35
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs1255004762; hg19: chr5-172517742;