1-31626924-A-G

Variant names:

• chr1-31626924-A-G
• rs2271933
• NM_001525.3:c.1222A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001525.3(HCRTR1):​c.1222A>G​(p.Ile408Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 1,613,344 control chromosomes in the GnomAD database, including 282,591 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.50 (20918 hom., cov: 32)
  • Exomes 𝑓: 0.59 (261673 hom.)
• Consequence: HCRTR1 NM_001525.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84
• Publications: 67 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.4532186E-5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.607 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCRTR1	NM_001525.3	MANE Select	c.1222A>G	p.Ile408Val	missense	Exon 9 of 9	NP_001516.2	O43613

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCRTR1	ENST00000403528.7	TSL:5 MANE Select	c.1222A>G	p.Ile408Val	missense	Exon 9 of 9	ENSP00000384387.2	O43613
	HCRTR1	ENST00000373706.9	TSL:1	c.1222A>G	p.Ile408Val	missense	Exon 7 of 7	ENSP00000362810.5	O43613
	HCRTR1	ENST00000373705.1	TSL:1	c.1087+1806A>G		intron	N/A	ENSP00000362809.1	A6NMV7

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76447 AN: 151896 Hom.: 20912 Cov.: 32

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.594

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.525

GnomAD2 exomes AF: 0.556 AC: 139595 AN: 251106 AF XY: 0.570

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.517

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.251

Gnomad FIN exome AF: 0.624

Gnomad NFE exome AF: 0.617

Gnomad OTH exome AF: 0.576

GnomAD4 exome AF: 0.593 AC: 865889 AN: 1461330 Hom.: 261673 Cov.: 55 AF XY: 0.595 AC XY: 432931 AN XY: 727006

African (AFR) AF: 0.294 AC: 9858 AN: 33476

American (AMR) AF: 0.516 AC: 23077 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 15795 AN: 26132

East Asian (EAS) AF: 0.238 AC: 9435 AN: 39692

South Asian (SAS) AF: 0.629 AC: 54225 AN: 86256

European-Finnish (FIN) AF: 0.618 AC: 32722 AN: 52944

Middle Eastern (MID) AF: 0.588 AC: 3390 AN: 5762

European-Non Finnish (NFE) AF: 0.615 AC: 683498 AN: 1111962

Other (OTH) AF: 0.561 AC: 33889 AN: 60384

GnomAD4 genome AF: 0.503 AC: 76470 AN: 152014 Hom.: 20918 Cov.: 32 AF XY: 0.503 AC XY: 37367 AN XY: 74304

African (AFR) AF: 0.299 AC: 12377 AN: 41454

American (AMR) AF: 0.515 AC: 7868 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.594 AC: 2061 AN: 3470

East Asian (EAS) AF: 0.241 AC: 1245 AN: 5166

South Asian (SAS) AF: 0.599 AC: 2878 AN: 4802

European-Finnish (FIN) AF: 0.625 AC: 6587 AN: 10540

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.612 AC: 41594 AN: 67982

Other (OTH) AF: 0.519 AC: 1097 AN: 2114

Alfa AF: 0.573 Hom.: 105247

Bravo AF: 0.486

TwinsUK AF: 0.622 AC: 2307

ALSPAC AF: 0.614 AC: 2365

ESP6500AA AF: 0.310 AC: 1364

ESP6500EA AF: 0.614 AC: 5281

ExAC AF: 0.556 AC: 67531

Asia WGS AF: 0.409 AC: 1424 AN: 3478

EpiCase AF: 0.614

EpiControl AF: 0.618

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	10
DANN	Benign	0.72
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.000035	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.4	N
PhyloP100		1.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.075
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.28
ClinPred		0.00057	T
GERP RS		3.8
Varity_R		0.027
gMVP		0.059
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2271933; hg19: chr1-32092525; COSMIC: COSV65483431; COSMIC: COSV65483431;