rs75040538

Variant names:

• chr3-184038603-C-G
• rs75040538
• NM_001145143.1:c.964C>G

Variant summary

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

The NM_001145143.1(HTR3D):​c.964C>G​(p.Leu322Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 1,613,584 control chromosomes in the GnomAD database, including 3,686 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.057 (310 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3376 hom.)
• Consequence: HTR3D NM_001145143.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.455
• Publications: 12 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017104149).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTR3D	NM_001145143.1	c.964C>G	p.Leu322Val	missense_variant	Exon 7 of 8	ENST00000428798.7	NP_001138615.1
HTR3D	NM_001163646.2	c.1114C>G	p.Leu372Val	missense_variant	Exon 7 of 8		NP_001157118.1
HTR3D	NM_182537.3	c.589C>G	p.Leu197Val	missense_variant	Exon 5 of 6		NP_872343.2
HTR3D	NM_001410851.1	c.451C>G	p.Leu151Val	missense_variant	Exon 4 of 5		NP_001397780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTR3D	ENST00000428798.7	c.964C>G	p.Leu322Val	missense_variant	Exon 7 of 8	5	NM_001145143.1	ENSP00000405409.2
HTR3D	ENST00000382489.3	c.1114C>G	p.Leu372Val	missense_variant	Exon 7 of 8	1		ENSP00000371929.3
HTR3D	ENST00000334128.6	c.589C>G	p.Leu197Val	missense_variant	Exon 5 of 6	1		ENSP00000334315.2
HTR3D	ENST00000453435.1	c.451C>G	p.Leu151Val	missense_variant	Exon 3 of 4	1		ENSP00000389268.1

Frequencies

GnomAD3 genomes AF: 0.0573 AC: 8717 AN: 152158 Hom.: 308 Cov.: 32

Gnomad AFR AF: 0.0401

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0537

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0549

Gnomad OTH AF: 0.0629

GnomAD2 exomes AF: 0.0684 AC: 17038 AN: 249082 AF XY: 0.0708

Gnomad AFR exome AF: 0.0409

Gnomad AMR exome AF: 0.0391

Gnomad ASJ exome AF: 0.0947

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.0478

Gnomad NFE exome AF: 0.0559

Gnomad OTH exome AF: 0.0694

GnomAD4 exome AF: 0.0612 AC: 89482 AN: 1461308 Hom.: 3376 Cov.: 88 AF XY: 0.0623 AC XY: 45259 AN XY: 726906

African (AFR) AF: 0.0375 AC: 1256 AN: 33466

American (AMR) AF: 0.0412 AC: 1840 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0937 AC: 2447 AN: 26118

East Asian (EAS) AF: 0.195 AC: 7725 AN: 39670

South Asian (SAS) AF: 0.106 AC: 9111 AN: 86214

European-Finnish (FIN) AF: 0.0484 AC: 2582 AN: 53362

Middle Eastern (MID) AF: 0.0643 AC: 365 AN: 5678

European-Non Finnish (NFE) AF: 0.0540 AC: 60000 AN: 1111768

Other (OTH) AF: 0.0689 AC: 4156 AN: 60340

GnomAD4 genome AF: 0.0573 AC: 8722 AN: 152276 Hom.: 310 Cov.: 32 AF XY: 0.0578 AC XY: 4305 AN XY: 74434

African (AFR) AF: 0.0402 AC: 1673 AN: 41566

American (AMR) AF: 0.0536 AC: 820 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 358 AN: 3470

East Asian (EAS) AF: 0.164 AC: 844 AN: 5154

South Asian (SAS) AF: 0.115 AC: 555 AN: 4830

European-Finnish (FIN) AF: 0.0525 AC: 557 AN: 10618

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0549 AC: 3736 AN: 68026

Other (OTH) AF: 0.0622 AC: 131 AN: 2106

Alfa AF: 0.0585 Hom.: 96

Bravo AF: 0.0559

TwinsUK AF: 0.0480 AC: 178

ALSPAC AF: 0.0464 AC: 179

ESP6500AA AF: 0.0438 AC: 193

ESP6500EA AF: 0.0592 AC: 509

ExAC AF: 0.0687 AC: 8342

Asia WGS AF: 0.133 AC: 463 AN: 3478

EpiCase AF: 0.0597

EpiControl AF: 0.0650

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.0022	.;.;T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.081	N
LIST_S2	Uncertain	0.88	D;D;D;D
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.5	.;.;M;.
PhyloP100		0.46
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.21	T;T;T;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.94	P;.;D;P
Vest4		0.13
MPC		0.67
ClinPred		0.0099	T
GERP RS		1.8
Varity_R		0.063
gMVP		0.053
Mutation Taster		=100/0	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: rs75040538; hg19: chr3-183756391; COSMIC: COSV61914742;