NM_000524.4:c.659G>A

Variant names:

• chr5-63961061-C-T
• NM_000524.4:c.659G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000524.4(HTR1A):​c.659G>A​(p.Arg220Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 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. R220L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (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]

ENSG00000248285 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18699917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTR1A	NM_000524.4	c.659G>A	p.Arg220Gln	missense_variant	Exon 1 of 1	ENST00000323865.5	NP_000515.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTR1A	ENST00000323865.5	c.659G>A	p.Arg220Gln	missense_variant	Exon 1 of 1	6	NM_000524.4	ENSP00000316244.4
ENSG00000248285	ENST00000502882.1	n.97-3046G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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: 0.00

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	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.070
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.35	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.089
Sift	Benign	1.0	T
Sift4G	Benign	0.39	T
Polyphen		0.75	P
Vest4		0.28
MutPred		0.50		Loss of methylation at R220 (P = 0.0253);
MVP		0.72
MPC		1.2
ClinPred		0.82	D
GERP RS		4.7
Varity_R		0.084
gMVP		0.54

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: chr5-63256888; COSMIC: COSV60500164; COSMIC: COSV60500164;