5-148548662-C-T

Variant names:

• chr5-148548662-C-T
• rs2278392
• NM_000870.7:c.353+6G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000870.7(HTR4):​c.353+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,591,338 control chromosomes in the GnomAD database, including 16,787 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (4262 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12525 hom.)
• Consequence: HTR4 NM_000870.7 splice_region, intron
• Scores: Splicing: ADA: 0.0001418
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0990
• Publications: 17 publications found

Genes affected

HTR4 (HGNC:5299): (5-hydroxytryptamine receptor 4) This gene is a member of the family of serotonin receptors, which are G protein coupled receptors that stimulate cAMP production in response to serotonin (5-hydroxytryptamine). The gene product is a glycosylated transmembrane protein that functions in both the peripheral and central nervous system to modulate the release of various neurotransmitters. Multiple transcript variants encoding proteins with distinct C-terminal sequences have been described. [provided by RefSeq, May 2010]

ENSG00000300418 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTR4	NM_000870.7	c.353+6G>A		splice_region_variant, intron_variant	Intron 4 of 6	ENST00000377888.8	NP_000861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTR4	ENST00000377888.8	c.353+6G>A		splice_region_variant, intron_variant	Intron 4 of 6	1	NM_000870.7	ENSP00000367120.4

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30378 AN: 152026 Hom.: 4257 Cov.: 32

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.0825

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.0988

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.154 AC: 33757 AN: 219590 AF XY: 0.145

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.0921

Gnomad EAS exome AF: 0.286

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0956

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.117 AC: 168589 AN: 1439194 Hom.: 12525 Cov.: 32 AF XY: 0.117 AC XY: 83306 AN XY: 714316

African (AFR) AF: 0.397 AC: 12953 AN: 32596

American (AMR) AF: 0.211 AC: 8835 AN: 41970

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 2295 AN: 25836

East Asian (EAS) AF: 0.285 AC: 10868 AN: 38132

South Asian (SAS) AF: 0.154 AC: 12877 AN: 83370

European-Finnish (FIN) AF: 0.116 AC: 6058 AN: 52346

Middle Eastern (MID) AF: 0.130 AC: 745 AN: 5740

European-Non Finnish (NFE) AF: 0.0966 AC: 106189 AN: 1099670

Other (OTH) AF: 0.130 AC: 7769 AN: 59534

GnomAD4 genome AF: 0.200 AC: 30417 AN: 152144 Hom.: 4262 Cov.: 32 AF XY: 0.200 AC XY: 14843 AN XY: 74394

African (AFR) AF: 0.395 AC: 16375 AN: 41486

American (AMR) AF: 0.200 AC: 3063 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0825 AC: 286 AN: 3468

East Asian (EAS) AF: 0.283 AC: 1460 AN: 5162

South Asian (SAS) AF: 0.146 AC: 704 AN: 4826

European-Finnish (FIN) AF: 0.118 AC: 1249 AN: 10598

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.0988 AC: 6721 AN: 68010

Other (OTH) AF: 0.188 AC: 396 AN: 2108

Alfa AF: 0.133 Hom.: 2395

Bravo AF: 0.214

Asia WGS AF: 0.200 AC: 693 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	16
DANN	Benign	0.48
PhyloP100		0.099
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.050		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: rs2278392; hg19: chr5-147928225; COSMIC: COSV58799207; COSMIC: COSV58799207;