1-31623620-G-A

Variant names:

• chr1-31623620-G-A
• rs7516785
• NM_001525.3:c.836G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R279W) has been classified as Uncertain significance.

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.37
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -20 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 VariationId is 783281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.074 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCRTR1	NM_001525.3	MANE Select	c.836G>A	p.Arg279Gln	missense	Exon 7 of 9	NP_001516.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCRTR1	ENST00000403528.7	TSL:5 MANE Select	c.836G>A	p.Arg279Gln	missense	Exon 7 of 9	ENSP00000384387.2
	HCRTR1	ENST00000373706.9	TSL:1	c.836G>A	p.Arg279Gln	missense	Exon 5 of 7	ENSP00000362810.5
	HCRTR1	ENST00000373705.1	TSL:1	c.836G>A	p.Arg279Gln	missense	Exon 5 of 7	ENSP00000362809.1

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

GnomAD2 exomes AF: 0.00587 AC: 1470 AN: 250576 AF XY: 0.00403

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 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

African (AFR) AF: 0.0753 AC: 2522 AN: 33478

American (AMR) AF: 0.00398 AC: 178 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53096

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.000103 AC: 115 AN: 1111996

Other (OTH) AF: 0.00518 AC: 313 AN: 60390

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

African (AFR) AF: 0.0762 AC: 3168 AN: 41556

American (AMR) AF: 0.00948 AC: 145 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68036

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00736 Hom.: 10

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.18
Sift	Benign	0.063	T
Sift4G	Benign	0.072	T
Polyphen		0.98	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
Mutation Taster		=97/3	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: rs7516785; hg19: chr1-32089221;