chr1-31621503-A-C

Variant names:

• chr1-31621503-A-C
• NM_001525.3:c.649A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001525.3(HCRTR1):​c.649A>C​(p.Ser217Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,600 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. S217G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HCRTR1 NM_001525.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCRTR1	NM_001525.3	c.649A>C	p.Ser217Arg	missense_variant	Exon 6 of 9	ENST00000403528.7	NP_001516.2
HCRTR1	XM_024446605.2	c.649A>C	p.Ser217Arg	missense_variant	Exon 7 of 11		XP_024302373.1
HCRTR1	XM_017001107.2	c.649A>C	p.Ser217Arg	missense_variant	Exon 4 of 7		XP_016856596.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCRTR1	ENST00000403528.7	c.649A>C	p.Ser217Arg	missense_variant	Exon 6 of 9	5	NM_001525.3	ENSP00000384387.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461600 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727128

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;T;.
Eigen	Benign	-0.058
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T;.;T
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.014	D;D;D
Sift4G	Benign	0.36	T;T;T
Polyphen		0.019	B;B;B
Vest4		0.77
MutPred		0.61		Loss of glycosylation at S217 (P = 0.0561);Loss of glycosylation at S217 (P = 0.0561);Loss of glycosylation at S217 (P = 0.0561);
MVP		0.80
MPC		0.37
ClinPred		0.92	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-32087104;