Variant chr1-31621522-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001525.3(HCRTR1):c.668C>T(p.Thr223Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,614,132 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.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

HCRTR1
NM_001525.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.48

Variant links:

Genes affected

HCRTR1 (HGNC:4848): (hypocretin receptor 1) The protein encoded by this gene is a G-protein coupled receptor involved in the regulation of feeding behavior. The encoded protein selectively binds the hypothalamic neuropeptide orexin A. A related gene (HCRTR2) encodes a G-protein coupled receptor that binds orexin A and orexin B. [provided by RefSeq, Jan 2009]

HCRTR1 links:

HCRTR1 (HGNC:):

HCRTR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.26378673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCRTR1	NM_001525.3 linkuse as main transcript	c.668C>T	p.Thr223Ile	missense_variant	6/9	ENST00000403528.7	NP_001516.2	O43613
HCRTR1	XM_024446605.2 linkuse as main transcript	c.668C>T	p.Thr223Ile	missense_variant	7/11		XP_024302373.1
HCRTR1	XM_017001107.2 linkuse as main transcript	c.668C>T	p.Thr223Ile	missense_variant	4/7		XP_016856596.1	A6NMV7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCRTR1	ENST00000403528.7 linkuse as main transcript	c.668C>T	p.Thr223Ile	missense_variant	6/9	5	NM_001525.3	ENSP00000384387.2		O43613

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251454

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000740

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000165

AC:

241

AN:

1461778

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

115

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000562

Gnomad4 NFE exome

AF:

0.000180

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2024

The c.668C>T (p.T223I) alteration is located in exon 6 (coding exon 4) of the HCRTR1 gene. This alteration results from a C to T substitution at nucleotide position 668, causing the threonine (T) at amino acid position 223 to be replaced by an isoleucine (I). 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

Uncertain

0.55

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.032

T;T;.

Eigen

Benign

-0.013

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;.;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.82

L;L;.

PrimateAI

Uncertain

0.70

PROVEAN

Benign

1.8

N;N;N

REVEL

Uncertain

0.41

Sift

Benign

0.62

T;T;T

Sift4G

Benign

0.51

T;T;T

Polyphen

0.067

B;B;B

Vest4

0.62

MVP

0.83

MPC

0.39

ClinPred

0.11

GERP RS

5.0

Varity_R

0.79

gMVP

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over