rs34118353

Variant names:

• chr5-63961168-G-A
• rs34118353
• NM_000524.4:c.552C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BS1 BS2

The NM_000524.4(HTR1A):​c.552C>T​(p.Pro184Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,614,156 control chromosomes in the GnomAD database, including 338 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.019 (52 hom., cov: 33)
  • Exomes 𝑓: 0.018 (286 hom.)
• Consequence: HTR1A NM_000524.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.541
• Publications: 9 publications found

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]

HTR1A Gene-Disease associations (from GenCC):

• menstrual cycle-dependent periodic fever

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000248285 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP7: Synonymous conserved (PhyloP=0.541 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0189 (2884/152336) while in subpopulation EAS AF = 0.0356 (184/5164). AF 95% confidence interval is 0.0314. There are 52 homozygotes in GnomAd4. There are 1405 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2884 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000524.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR1A	NM_000524.4	MANE Select	c.552C>T	p.Pro184Pro	synonymous	Exon 1 of 1	NP_000515.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR1A	ENST00000323865.5	TSL:6 MANE Select	c.552C>T	p.Pro184Pro	synonymous	Exon 1 of 1	ENSP00000316244.4
	ENSG00000248285	ENST00000502882.1	TSL:2	n.97-3153C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2881 AN: 152218 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.0355

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0197 AC: 4905 AN: 249262 AF XY: 0.0204

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.0370

Gnomad FIN exome AF: 0.00402

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0208

GnomAD4 exome AF: 0.0181 AC: 26492 AN: 1461820 Hom.: 286 Cov.: 31 AF XY: 0.0185 AC XY: 13443 AN XY: 727208

African (AFR) AF: 0.0185 AC: 620 AN: 33480

American (AMR) AF: 0.0214 AC: 955 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 385 AN: 26136

East Asian (EAS) AF: 0.0314 AC: 1247 AN: 39700

South Asian (SAS) AF: 0.0317 AC: 2736 AN: 86258

European-Finnish (FIN) AF: 0.00358 AC: 191 AN: 53350

Middle Eastern (MID) AF: 0.0205 AC: 118 AN: 5768

European-Non Finnish (NFE) AF: 0.0172 AC: 19091 AN: 1112010

Other (OTH) AF: 0.0190 AC: 1149 AN: 60394

GnomAD4 genome AF: 0.0189 AC: 2884 AN: 152336 Hom.: 52 Cov.: 33 AF XY: 0.0189 AC XY: 1405 AN XY: 74486

African (AFR) AF: 0.0177 AC: 738 AN: 41586

American (AMR) AF: 0.0287 AC: 440 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3470

East Asian (EAS) AF: 0.0356 AC: 184 AN: 5164

South Asian (SAS) AF: 0.0305 AC: 147 AN: 4826

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0167 AC: 1139 AN: 68032

Other (OTH) AF: 0.0236 AC: 50 AN: 2116

Alfa AF: 0.0172 Hom.: 18

Bravo AF: 0.0219

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0190

EpiControl AF: 0.0188

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.1
DANN	Benign	0.91
PhyloP100		0.54
Mutation Taster		=97/3	polymorphism (auto)

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: rs34118353; hg19: chr5-63256995; COSMIC: COSV60499847; COSMIC: COSV60499847;