rs4458044

Variant names:

• chr17-45796361-G-C
• rs4458044
• NM_004382.5:c.34-10649G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004382.5(CRHR1):​c.34-10649G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,102 control chromosomes in the GnomAD database, including 4,455 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (4455 hom., cov: 32)
• Consequence: CRHR1 NM_004382.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0110
• Publications: 23 publications found

Genes affected

CRHR1 (HGNC:2357): (corticotropin releasing hormone receptor 1) This gene encodes a G-protein coupled receptor that binds neuropeptides of the corticotropin releasing hormone family that are major regulators of the hypothalamic-pituitary-adrenal pathway. The encoded protein is essential for the activation of signal transduction pathways that regulate diverse physiological processes including stress, reproduction, immune response and obesity. Alternative splicing results in multiple transcript variants. Naturally-occurring readthrough transcription between this gene and upstream GeneID:147081 results in transcripts that encode isoforms that share similarity with the products of this gene. [provided by RefSeq, Aug 2016]

LINC02210-CRHR1 (HGNC:51483): (LINC02210-CRHR1 readthrough) This locus represents naturally occurring readthrough transcription between neighboring genes CRHR1-IT1, CRHR1 intronic transcript 1 (Gene ID: 147081) and CRHR1, corticotropin releasing hormone receptor 1 (Gene ID: 1394) on chromosome 17. The readthrough transcript encodes a protein that shares sequence identity with the product of the CRHR1 gene. [provided by RefSeq, Dec 2016]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRHR1	NM_004382.5	c.34-10649G>C		intron_variant	Intron 1 of 12	ENST00000314537.10	NP_004373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRHR1	ENST00000314537.10	c.34-10649G>C		intron_variant	Intron 1 of 12	1	NM_004382.5	ENSP00000326060.6
LINC02210-CRHR1	ENST00000634540.1	c.-492-10649G>C		intron_variant	Intron 3 of 14	2		ENSP00000488912.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32207 AN: 151984 Hom.: 4445 Cov.: 32

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.185

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.212 AC: 32210 AN: 152102 Hom.: 4455 Cov.: 32 AF XY: 0.224 AC XY: 16645 AN XY: 74354

African (AFR) AF: 0.0469 AC: 1946 AN: 41504

American (AMR) AF: 0.275 AC: 4197 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 734 AN: 3470

East Asian (EAS) AF: 0.293 AC: 1513 AN: 5162

South Asian (SAS) AF: 0.313 AC: 1510 AN: 4822

European-Finnish (FIN) AF: 0.445 AC: 4699 AN: 10564

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.248 AC: 16846 AN: 67978

Other (OTH) AF: 0.183 AC: 386 AN: 2112

Alfa AF: 0.233 Hom.: 593

Bravo AF: 0.189

Asia WGS AF: 0.290 AC: 1009 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.55
PhyloP100		0.011
Mutation Taster		=100/0	polymorphism (auto)

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: rs4458044; hg19: chr17-43873727;