rs7516785

chr1-31623620-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001525.3(HCRTR1):c.836G>A(p.Arg279Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00404 in 1,613,850 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.022 (110 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (121 hom.)
• Consequence: HCRTR1 NM_001525.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.37

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022182167).
• BP6: Variant 1-31623620-G-A is Benign according to our data. Variant chr1-31623620-G-A is described in ClinVar as [Benign]. Clinvar id is 783281.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.074 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCRTR1	NM_001525.3	c.836G>A	p.Arg279Gln	missense_variant	7/9	ENST00000403528.7
HCRTR1	XM_024446605.2	c.836G>A	p.Arg279Gln	missense_variant	8/11
HCRTR1	XM_017001107.2	c.836G>A	p.Arg279Gln	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCRTR1	ENST00000403528.7	c.836G>A	p.Arg279Gln	missense_variant	7/9	5	NM_001525.3	P1

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3346 AN: 152188 Hom.: 108 Cov.: 32

Gnomad AFR AF: 0.0761

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00587 AC: 1470 AN: 250576 Hom.: 49 AF XY: 0.00403 AC XY: 547 AN XY: 135676

Gnomad AFR exome AF: 0.0805

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00216 AC: 3158 AN: 1461544 Hom.: 121 Cov.: 31 AF XY: 0.00191 AC XY: 1389 AN XY: 727072

Gnomad4 AFR exome AF: 0.0753

Gnomad4 AMR exome AF: 0.00398

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.00518

GnomAD4 genome AF: 0.0221 AC: 3361 AN: 152306 Hom.: 110 Cov.: 32 AF XY: 0.0215 AC XY: 1603 AN XY: 74480

Gnomad4 AFR AF: 0.0762

Gnomad4 AMR AF: 0.00948

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00651 Hom.: 9

Bravo AF: 0.0252

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0763 AC: 336

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00736 AC: 894

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.095	T;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.78	T;.;T
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	0.86	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.49	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.063	T;T;T
Sift4G	Benign	0.072	T;T;T
Polyphen		0.98	D;D;D
Vest4		0.14
MVP		0.80
MPC		0.82
ClinPred		0.045	T
GERP RS		3.9
Varity_R		0.16
gMVP		0.56

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

Other links and lift over

dbSNP: rs7516785; hg19: chr1-32089221;