5-63961426-C-T

Variant names:

• chr5-63961426-C-T
• rs6294
• NM_000524.4:c.294G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000524.4(HTR1A):​c.294G>A​(p.Val98Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,613,856 control chromosomes in the GnomAD database, including 2,792 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 0.077 (1429 hom., cov: 33)
  • Exomes 𝑓: 0.0091 (1363 hom.)
• Consequence: HTR1A NM_000524.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.208
• Publications: 19 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP7: Synonymous conserved (PhyloP=-0.208 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTR1A	NM_000524.4	c.294G>A	p.Val98Val	synonymous_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.294G>A	p.Val98Val	synonymous_variant	Exon 1 of 1	6	NM_000524.4	ENSP00000316244.4
ENSG00000248285	ENST00000502882.1	n.97-3411G>A		intron_variant	Intron 1 of 1	2
HTR1A	ENST00000506598.1	c.*169G>A		downstream_gene_variant		4		ENSP00000423433.1

Frequencies

GnomAD3 genomes AF: 0.0767 AC: 11677 AN: 152200 Hom.: 1427 Cov.: 33

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0342

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.0621

GnomAD2 exomes AF: 0.0222 AC: 5534 AN: 249836 AF XY: 0.0168

Gnomad AFR exome AF: 0.265

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.00398

Gnomad EAS exome AF: 0.0356

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000850

Gnomad OTH exome AF: 0.00968

GnomAD4 exome AF: 0.00911 AC: 13311 AN: 1461536 Hom.: 1363 Cov.: 31 AF XY: 0.00815 AC XY: 5928 AN XY: 727054

African (AFR) AF: 0.274 AC: 9154 AN: 33450

American (AMR) AF: 0.0136 AC: 607 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00364 AC: 95 AN: 26128

East Asian (EAS) AF: 0.0366 AC: 1451 AN: 39652

South Asian (SAS) AF: 0.00206 AC: 178 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5768

European-Non Finnish (NFE) AF: 0.000503 AC: 559 AN: 1111858

Other (OTH) AF: 0.0198 AC: 1193 AN: 60386

GnomAD4 genome AF: 0.0768 AC: 11698 AN: 152320 Hom.: 1429 Cov.: 33 AF XY: 0.0743 AC XY: 5535 AN XY: 74468

African (AFR) AF: 0.261 AC: 10843 AN: 41556

American (AMR) AF: 0.0300 AC: 459 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.0341 AC: 176 AN: 5164

South Asian (SAS) AF: 0.00434 AC: 21 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68038

Other (OTH) AF: 0.0614 AC: 130 AN: 2116

Alfa AF: 0.0290 Hom.: 729

Bravo AF: 0.0895

Asia WGS AF: 0.0300 AC: 103 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000892

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.6
DANN	Benign	0.92
PhyloP100		-0.21
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6294; hg19: chr5-63257253; COSMIC: COSV60500974; COSMIC: COSV60500974;