NM_001525.3:c.301C>A

Variant names:

• chr1-31619633-C-A
• rs745916428
• NM_001525.3:c.301C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001525.3(HCRTR1):​c.301C>A​(p.Pro101Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P101S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HCRTR1 NM_001525.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

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.301C>A	p.Pro101Thr	missense	Exon 4 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.301C>A	p.Pro101Thr	missense	Exon 4 of 9	ENSP00000384387.2	O43613
	HCRTR1	ENST00000373706.9	TSL:1	c.301C>A	p.Pro101Thr	missense	Exon 2 of 7	ENSP00000362810.5	O43613
	HCRTR1	ENST00000373705.1	TSL:1	c.301C>A	p.Pro101Thr	missense	Exon 2 of 7	ENSP00000362809.1	A6NMV7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461684 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.87		Gain of catalytic residue at P101 (P = 0.0203)
MVP		0.63
MPC		1.1
ClinPred		0.98	D
GERP RS		3.5
PromoterAI		-0.0042	Neutral
Varity_R		0.91
gMVP		0.73
Mutation Taster		=46/54	disease causing

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: rs745916428; hg19: chr1-32085234;