Genetic Variant HTR3E:p.Trp102Arg (chr3-184104206-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001256613.2(HTR3E):c.304T>A(p.Trp102Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HTR3E
NM_001256613.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.40

Publications

0 publications found

Variant links:

Genes affected

HTR3E (HGNC:24005): (5-hydroxytryptamine receptor 3E) This locus encodes a 5-hydroxytryptamine (serotonin) receptor subunit. The encoded protein, subunit E, may play a role in neurotransmission in myenteric neurons. Genes encoding subunits C, D and E form a cluster on chromosome 3. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Feb 2012]

HTR3E links:

HTR3E-AS1 (HGNC:41032): (HTR3E antisense RNA 1)

HTR3E-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256613.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HTR3E	NM_001256613.2	MANE Select	c.304T>A	p.Trp102Arg	missense	Exon 4 of 9	NP_001243542.1	A5X5Y0-1
HTR3E	NM_001256614.1		c.304T>A	p.Trp102Arg	missense	Exon 2 of 7	NP_001243543.1	A5X5Y0-6
HTR3E	NM_182589.2		c.349T>A	p.Trp117Arg	missense	Exon 3 of 8	NP_872395.2	A5X5Y0-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HTR3E	ENST00000415389.6	TSL:1 MANE Select	c.304T>A	p.Trp102Arg	missense	Exon 4 of 9	ENSP00000401444.2	A5X5Y0-1
HTR3E	ENST00000440596.2	TSL:1	c.304T>A	p.Trp102Arg	missense	Exon 2 of 7	ENSP00000406050.2	A5X5Y0-6
HTR3E	ENST00000335304.6	TSL:1	c.349T>A	p.Trp117Arg	missense	Exon 3 of 8	ENSP00000335511.2	A5X5Y0-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249134

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460180

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33352

American (AMR)

AF:

0.0000224

AC:

AN:

44570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39554

South Asian (SAS)

AF:

0.00

AC:

AN:

86052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111252

Other (OTH)

AF:

0.00

AC:

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

M_CAP

Benign

0.031

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.72

MutationAssessor

Pathogenic

3.9

PhyloP100

3.4

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-12

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.045

Polyphen

1.0

Vest4

0.63

MutPred

0.89

Gain of disorder (P = 0.0052)

MVP

0.95

MPC

0.47

ClinPred

0.96

GERP RS

3.5

Varity_R

0.75

gMVP

0.51

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over