chr1-31626924-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001525.3(HCRTR1):​c.1222A>T​(p.Ile408Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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: not found (cov: 32)
• Consequence: HCRTR1 NM_001525.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15651593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCRTR1	NM_001525.3	c.1222A>T	p.Ile408Phe	missense_variant	Exon 9 of 9	ENST00000403528.7	NP_001516.2
HCRTR1	XM_024446605.2	c.1222A>T	p.Ile408Phe	missense_variant	Exon 10 of 11		XP_024302373.1
HCRTR1	XM_017001107.2	c.1087+1806A>T		intron_variant	Intron 6 of 6		XP_016856596.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCRTR1	ENST00000403528.7	c.1222A>T	p.Ile408Phe	missense_variant	Exon 9 of 9	5	NM_001525.3	ENSP00000384387.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.046	T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.31	T;.
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N
PhyloP100		1.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.097
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.55	T;T
Polyphen		0.78	P;P
Vest4		0.12
MutPred		0.16		Loss of MoRF binding (P = 0.1021);Loss of MoRF binding (P = 0.1021);
MVP		0.57
MPC		0.61
ClinPred		0.60	D
GERP RS		3.8
Varity_R		0.097
gMVP		0.15
Mutation Taster		=92/8	polymorphism

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: rs2271933; hg19: chr1-32092525;