chr5-63961061-C-G

Position:

• chr5-63961061-C-G

Variant summary

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

The NM_000524.4(HTR1A):​c.659G>C​(p.Arg220Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R220L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HTR1A NM_000524.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.799

Genes affected

HTR1A (HGNC:5286): (5-hydroxytryptamine receptor 1A) This gene encodes a G protein-coupled receptor for 5-hydroxytryptamine (serotonin), and belongs to the 5-hydroxytryptamine receptor subfamily. Serotonin has been implicated in a number of physiologic processes and pathologic conditions. Inactivation of this gene in mice results in behavior consistent with an increased anxiety and stress response. Mutation in the promoter of this gene has been associated with menstrual cycle-dependent periodic fevers. [provided by RefSeq, Jun 2012]

(HGNC:):

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=0.38827103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR1A	NM_000524.4	c.659G>C	p.Arg220Pro	missense_variant	1/1	ENST00000323865.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR1A	ENST00000323865.5	c.659G>C	p.Arg220Pro	missense_variant	1/1		NM_000524.4	P1
	ENST00000502882.1	n.97-3046G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.11
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.021	D
Sift4G	Benign	0.15	T
Polyphen		0.046	B
Vest4		0.50
MutPred		0.60		Loss of MoRF binding (P = 0.0093);
MVP		0.79
MPC		0.97
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.91
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1800044; hg19: chr5-63256888;