NM_001525.3:c.614G>T

Variant names:

• chr1-31621078-G-T
• rs147546381
• NM_001525.3:c.614G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001525.3(HCRTR1):​c.614G>T​(p.Arg205Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R205H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HCRTR1 NM_001525.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30173495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCRTR1	NM_001525.3	c.614G>T	p.Arg205Leu	missense_variant	Exon 5 of 9	ENST00000403528.7	NP_001516.2
HCRTR1	XM_024446605.2	c.614G>T	p.Arg205Leu	missense_variant	Exon 6 of 11		XP_024302373.1
HCRTR1	XM_017001107.2	c.614G>T	p.Arg205Leu	missense_variant	Exon 3 of 7		XP_016856596.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCRTR1	ENST00000403528.7	c.614G>T	p.Arg205Leu	missense_variant	Exon 5 of 9	5	NM_001525.3	ENSP00000384387.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452112 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000218

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.82	T;.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.56	N;N;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.57
MutPred		0.43		Loss of catalytic residue at R205 (P = 0.0971);Loss of catalytic residue at R205 (P = 0.0971);Loss of catalytic residue at R205 (P = 0.0971);
MVP		0.24
MPC		0.42
ClinPred		0.097	T
GERP RS		-2.5
Varity_R		0.41
gMVP		0.59

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: rs147546381; hg19: chr1-32086679;