dbSNP rs41439244: HCRTR1:p.Arg281His (chr1-31623626-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001525.3(HCRTR1):c.842G>A(p.Arg281His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000713 in 1,613,918 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 1 hom. )

Consequence

HCRTR1
NM_001525.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.23

Publications

5 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008223832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCRTR1	NM_001525.3 link	c.842G>A	p.Arg281His	missense_variant	Exon 7 of 9	ENST00000403528.7	NP_001516.2	O43613
HCRTR1	XM_024446605.2 link	c.842G>A	p.Arg281His	missense_variant	Exon 8 of 11		XP_024302373.1
HCRTR1	XM_017001107.2 link	c.842G>A	p.Arg281His	missense_variant	Exon 5 of 7		XP_016856596.1	A6NMV7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCRTR1	ENST00000403528.7 link	c.842G>A	p.Arg281His	missense_variant	Exon 7 of 9	5	NM_001525.3	ENSP00000384387.2		O43613

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000702

AC:

176

AN:

250716

AF XY:

0.000612

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00412

Gnomad NFE exome

AF:

0.000574

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000735

AC:

1074

AN:

1461566

Hom.:

Cov.:

AF XY:

0.000732

AC XY:

532

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00392

AC:

208

AN:

53114

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000723

AC:

804

AN:

1111998

Other (OTH)

AF:

0.000546

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

132

198

264

330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000505

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41590

American (AMR)

AF:

0.000131

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000750

AC:

AN:

68032

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000540

Hom.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000741

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.061

T;T;.

Eigen

Benign

-0.064

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.84

T;.;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.0082

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.4

L;L;.

PhyloP100

3.2

PrimateAI

Benign

0.46

PROVEAN

Benign

0.27

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.62

T;T;T

Sift4G

Benign

0.23

T;T;T

Polyphen

0.083

B;B;B

Vest4

0.24

MVP

0.70

MPC

0.47

ClinPred

0.097

GERP RS

4.8

Varity_R

0.14

gMVP

0.53

Mutation Taster

=83/17

polymorphism

(source)

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over