Genetic Variant HTR3C:p.Asn163Lys (chr3-184056974-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_130770.3(HTR3C):c.489C>A(p.Asn163Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 1,610,726 control chromosomes in the GnomAD database, including 151,190 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.43 ( 14317 hom., cov: 32)

Exomes 𝑓: 0.43 ( 136873 hom. )

Consequence

HTR3C
NM_130770.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.779

Publications

54 publications found

Variant links:

Genes affected

HTR3C (HGNC:24003): (5-hydroxytryptamine receptor 3C) The product of this gene belongs to the ligand-gated ion channel receptor superfamily. This gene encodes subunit C of the type 3 receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor causes fast, depolarizing responses in neurons after activation. Genes encoding subunits C, D and E form a cluster on chromosome 3. [provided by RefSeq, Jul 2008]

HTR3C links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=5.896953E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTR3C	NM_130770.3 link	c.489C>A	p.Asn163Lys	missense_variant	Exon 5 of 9	ENST00000318351.2	NP_570126.2	Q8WXA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTR3C	ENST00000318351.2 link	c.489C>A	p.Asn163Lys	missense_variant	Exon 5 of 9	1	NM_130770.3	ENSP00000322617.1		Q8WXA8

Frequencies

GnomAD3 genomes

AF:

0.431

AC:

65421

AN:

151830

Hom.:

14299

Cov.:

show subpopulations

Gnomad AFR

AF:

0.409

Gnomad AMI

AF:

0.435

Gnomad AMR

AF:

0.466

Gnomad ASJ

AF:

0.455

Gnomad EAS

AF:

0.630

Gnomad SAS

AF:

0.372

Gnomad FIN

AF:

0.462

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.421

Gnomad OTH

AF:

0.408

GnomAD2 exomes

AF:

0.453

AC:

113543

AN:

250782

AF XY:

0.444

show subpopulations

Gnomad AFR exome

AF:

0.408

Gnomad AMR exome

AF:

0.551

Gnomad ASJ exome

AF:

0.459

Gnomad EAS exome

AF:

0.639

Gnomad FIN exome

AF:

0.464

Gnomad NFE exome

AF:

0.419

Gnomad OTH exome

AF:

0.442

GnomAD4 exome

AF:

0.430

AC:

627266

AN:

1458778

Hom.:

136873

Cov.:

AF XY:

0.427

AC XY:

309941

AN XY:

725708

show subpopulations

African (AFR)

AF:

0.414

AC:

13819

AN:

33400

American (AMR)

AF:

0.538

AC:

24028

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.453

AC:

11810

AN:

26074

East Asian (EAS)

AF:

0.611

AC:

24237

AN:

39656

South Asian (SAS)

AF:

0.370

AC:

31729

AN:

85866

European-Finnish (FIN)

AF:

0.465

AC:

24777

AN:

53294

Middle Eastern (MID)

AF:

0.432

AC:

2483

AN:

5752

European-Non Finnish (NFE)

AF:

0.421

AC:

467547

AN:

1109832

Other (OTH)

AF:

0.445

AC:

26836

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

16441

32882

49324

65765

82206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14516

29032

43548

58064

72580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.431

AC:

65470

AN:

151948

Hom.:

14317

Cov.:

AF XY:

0.435

AC XY:

32311

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.408

AC:

16910

AN:

41452

American (AMR)

AF:

0.467

AC:

7121

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

1580

AN:

3472

East Asian (EAS)

AF:

0.630

AC:

3245

AN:

5150

South Asian (SAS)

AF:

0.372

AC:

1789

AN:

4814

European-Finnish (FIN)

AF:

0.462

AC:

4866

AN:

10540

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.421

AC:

28580

AN:

67950

Other (OTH)

AF:

0.415

AC:

875

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1906

3813

5719

7626

9532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

618

1236

1854

2472

3090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.421

Hom.:

29901

Bravo

AF:

0.435

TwinsUK

AF:

0.416

AC:

1543

ALSPAC

AF:

0.421

AC:

1622

ESP6500AA

AF:

0.416

AC:

1833

ESP6500EA

AF:

0.426

AC:

3661

ExAC

AF:

0.445

AC:

54066

Asia WGS

AF:

0.540

AC:

1878

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.057

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0000059

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.88

PhyloP100

-0.78

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.3

REVEL

Benign

0.12

Sift

Benign

0.056

Sift4G

Benign

0.19

Polyphen

0.044

Vest4

0.074

MutPred

0.21

Gain of methylation at N163 (P = 0.0057);

MPC

0.048

ClinPred

0.0064

GERP RS

0.97

Varity_R

0.13

gMVP

0.026

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over