5-173090650-C-T

Variant names:

• chr5-173090650-C-T
• rs35768619
• NM_153607.3:c.471C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_153607.3(CREBRF):​c.471C>T​(p.Pro157Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,084 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0098 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (38 hom.)
• Consequence: CREBRF NM_153607.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.41
• Publications: 1 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-173090650-C-T is Benign according to our data. Variant chr5-173090650-C-T is described in ClinVar as Benign. ClinVar VariationId is 776103.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00981 (1494/152226) while in subpopulation AFR AF = 0.0338 (1405/41540). AF 95% confidence interval is 0.0324. There are 21 homozygotes in GnomAd4. There are 704 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1494 AD gene.

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.471C>T	p.Pro157Pro	synonymous	Exon 4 of 9	NP_705835.2	Q8IUR6-1
	CREBRF	NM_001168393.2		c.471C>T	p.Pro157Pro	synonymous	Exon 4 of 4	NP_001161865.1	Q8IUR6-2
	CREBRF	NM_001168394.2		c.471C>T	p.Pro157Pro	synonymous	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.471C>T	p.Pro157Pro	synonymous	Exon 4 of 9	ENSP00000296953.2	Q8IUR6-1
	CREBRF	ENST00000520420.5	TSL:1	c.471C>T	p.Pro157Pro	synonymous	Exon 4 of 4	ENSP00000428290.1	Q8IUR6-2
	CREBRF	ENST00000522692.5	TSL:1	c.471C>T	p.Pro157Pro	synonymous	Exon 4 of 4	ENSP00000431107.1	Q8IUR6-2

Frequencies

GnomAD3 genomes AF: 0.00977 AC: 1486 AN: 152108 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0337

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00263 AC: 660 AN: 251114 AF XY: 0.00195

Gnomad AFR exome AF: 0.0364

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00107 AC: 1569 AN: 1461858 Hom.: 38 Cov.: 32 AF XY: 0.000941 AC XY: 684 AN XY: 727232

African (AFR) AF: 0.0367 AC: 1228 AN: 33476

American (AMR) AF: 0.00165 AC: 74 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0000737 AC: 82 AN: 1111996

Other (OTH) AF: 0.00278 AC: 168 AN: 60392

GnomAD4 genome AF: 0.00981 AC: 1494 AN: 152226 Hom.: 21 Cov.: 32 AF XY: 0.00946 AC XY: 704 AN XY: 74426

African (AFR) AF: 0.0338 AC: 1405 AN: 41540

American (AMR) AF: 0.00451 AC: 69 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68006

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00508 Hom.: 8

Bravo AF: 0.0114

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.45
DANN	Benign	0.48
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs35768619; hg19: chr5-172517653;