NM_004382.5:c.23G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004382.5(CRHR1):c.23G>A(p.Arg8His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CRHR1
NM_004382.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.490

Publications

0 publications found

Variant links:

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]

CRHR1 links:

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]

LINC02210-CRHR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14359027).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRHR1	NM_004382.5 link	c.23G>A	p.Arg8His	missense_variant	Exon 1 of 13	ENST00000314537.10	NP_004373.2	P34998-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRHR1	ENST00000314537.10 link	c.23G>A	p.Arg8His	missense_variant	Exon 1 of 13	1	NM_004382.5	ENSP00000326060.6		P34998-2
LINC02210-CRHR1	ENST00000634540.1 link	c.-492-22443G>A		intron_variant	Intron 3 of 14	2		ENSP00000488912.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1401422

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692694

African (AFR)

AF:

0.00

AC:

AN:

30822

American (AMR)

AF:

0.00

AC:

AN:

37444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24926

East Asian (EAS)

AF:

0.00

AC:

AN:

35220

South Asian (SAS)

AF:

0.00

AC:

AN:

79488

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081972

Other (OTH)

AF:

0.00

AC:

AN:

57976

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 15, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.23G>A (p.R8H) alteration is located in exon 1 (coding exon 1) of the CRHR1 gene. This alteration results from a G to A substitution at nucleotide position 23, causing the arginine (R) at amino acid position 8 to be replaced by a histidine (H). 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

0.18

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.047

T;.;.;.;.;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.25

LIST_S2

Uncertain

0.87

D;D;D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.14

T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

.;.;N;N;N;N

PhyloP100

0.49

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.33

.;.;N;N;.;N

REVEL

Benign

0.044

Sift

Benign

0.18

.;.;T;D;.;T

Sift4G

Uncertain

0.012

D;T;T;T;T;T

Polyphen

0.88, 0.62, 0.13, 0.70

.;.;P;P;B;P

Vest4

0.23

MutPred

0.36

Loss of methylation at R8 (P = 0.0103);Loss of methylation at R8 (P = 0.0103);Loss of methylation at R8 (P = 0.0103);Loss of methylation at R8 (P = 0.0103);Loss of methylation at R8 (P = 0.0103);Loss of methylation at R8 (P = 0.0103);

MVP

0.45

MPC

0.78

ClinPred

0.087

GERP RS

-1.1

PromoterAI

0.034

Neutral

(source)

Varity_R

0.041

gMVP

0.53

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over