rs73183412

Positions:

• chr3-184036490-C-G
• chr3-184036490-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001145143.1(HTR3D):​c.313C>G​(p.Pro105Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0649 in 1,613,946 control chromosomes in the GnomAD database, including 3,823 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.064 (346 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3477 hom.)
• Consequence: HTR3D NM_001145143.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.04

Genes affected

HTR3D (HGNC:24004): (5-hydroxytryptamine receptor 3D) The protein encoded this gene belongs to the ligand-gated ion channel receptor superfamily. This gene encodes subunit D of the type 3 receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a mitogen and a hormone. This hormone has been linked to neuropsychiatric disorders, including anxiety, depression, and migraine. Serotonin receptors causes fast and depolarizing responses in neurons following activation. The genes encoding subunits C, D and E of this type 3 receptor form a cluster on chromosome 3. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001760155).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR3D	NM_001145143.1	c.313C>G	p.Pro105Ala	missense_variant	4/8	ENST00000428798.7	NP_001138615.1
HTR3D	NM_001163646.2	c.496C>G	p.Pro166Ala	missense_variant	4/8		NP_001157118.1
HTR3D	NM_182537.3	c.91C>G	p.Pro31Ala	missense_variant	3/6		NP_872343.2
HTR3D	NM_001410851.1	c.3+1268C>G		intron_variant			NP_001397780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR3D	ENST00000428798.7	c.313C>G	p.Pro105Ala	missense_variant	4/8	5	NM_001145143.1	ENSP00000405409.2
HTR3D	ENST00000382489.3	c.496C>G	p.Pro166Ala	missense_variant	4/8	1		ENSP00000371929.3
HTR3D	ENST00000334128.6	c.91C>G	p.Pro31Ala	missense_variant	3/6	1		ENSP00000334315.2
HTR3D	ENST00000453435.1	c.3+1268C>G		intron_variant		1		ENSP00000389268.1

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 9718 AN: 152160 Hom.: 347 Cov.: 33

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.0578

Gnomad SAS AF: 0.0427

Gnomad FIN AF: 0.0347

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0632

Gnomad OTH AF: 0.0753

GnomAD3 exomes AF: 0.0732 AC: 18387 AN: 251358 Hom.: 823 AF XY: 0.0701 AC XY: 9517 AN XY: 135842

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.137

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.0543

Gnomad SAS exome AF: 0.0461

Gnomad FIN exome AF: 0.0392

Gnomad NFE exome AF: 0.0654

Gnomad OTH exome AF: 0.0826

GnomAD4 exome AF: 0.0650 AC: 95030 AN: 1461668 Hom.: 3477 Cov.: 33 AF XY: 0.0645 AC XY: 46909 AN XY: 727128

Gnomad4 AFR exome AF: 0.0514

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.0610

Gnomad4 SAS exome AF: 0.0478

Gnomad4 FIN exome AF: 0.0418

Gnomad4 NFE exome AF: 0.0624

Gnomad4 OTH exome AF: 0.0708

GnomAD4 genome AF: 0.0638 AC: 9712 AN: 152278 Hom.: 346 Cov.: 33 AF XY: 0.0633 AC XY: 4715 AN XY: 74458

Gnomad4 AFR AF: 0.0498

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.0577

Gnomad4 SAS AF: 0.0433

Gnomad4 FIN AF: 0.0347

Gnomad4 NFE AF: 0.0632

Gnomad4 OTH AF: 0.0740

Alfa AF: 0.0707 Hom.: 288

Bravo AF: 0.0709

TwinsUK AF: 0.0623 AC: 231

ALSPAC AF: 0.0677 AC: 261

ESP6500AA AF: 0.0449 AC: 198

ESP6500EA AF: 0.0673 AC: 579

ExAC AF: 0.0705 AC: 8558

Asia WGS AF: 0.0450 AC: 159 AN: 3478

EpiCase AF: 0.0727

EpiControl AF: 0.0687

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.47
DEOGEN2	Benign	0.0022	.;.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.51	T;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.90	.;.;L
PROVEAN	Benign	-0.37	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.32	T;T;T
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		0.97	D;.;B
Vest4		0.23
MPC		0.16
ClinPred		0.026	T
GERP RS		5.0
Varity_R		0.061
gMVP		0.023

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

LitVar

Other links and lift over

dbSNP: rs73183412; hg19: chr3-183754278; COSMIC: COSV61914206;