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GeneBe

11-113931385-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006028.5(HTR3B):c.215A>T(p.Asp72Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000103 in 1,449,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

HTR3B
NM_006028.5 missense, splice_region

Scores

10
5
4
Splicing: ADA: 0.8109
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.70
Variant links:
Genes affected
HTR3B (HGNC:5298): (5-hydroxytryptamine receptor 3B) The product of this gene belongs to the ligand-gated ion channel receptor superfamily. This gene encodes subunit B 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. It is not functional as a homomeric complex, but a pentaheteromeric complex with subunit A (HTR3A) displays the full functional features of this receptor. [provided by RefSeq, Aug 2011]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HTR3BNM_006028.5 linkuse as main transcriptc.215A>T p.Asp72Val missense_variant, splice_region_variant 3/9 ENST00000260191.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HTR3BENST00000260191.8 linkuse as main transcriptc.215A>T p.Asp72Val missense_variant, splice_region_variant 3/91 NM_006028.5 P2O95264-1
HTR3BENST00000537778.5 linkuse as main transcriptc.182A>T p.Asp61Val missense_variant, splice_region_variant 2/81 A2O95264-2
HTR3BENST00000543092.1 linkuse as main transcriptc.2A>T p.Ter1= coding_sequence_variant 1/53

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000532
AC:
13
AN:
244426
Hom.:
0
AF XY:
0.0000303
AC XY:
4
AN XY:
132076
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000369
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000168
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1449658
Hom.:
0
Cov.:
28
AF XY:
0.00000693
AC XY:
5
AN XY:
721318
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000328
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000189
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 29, 2022The c.215A>T (p.D72V) alteration is located in exon 3 (coding exon 3) of the HTR3B gene. This alteration results from a A to T substitution at nucleotide position 215, causing the aspartic acid (D) at amino acid position 72 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.32
Cadd
Pathogenic
31
Dann
Uncertain
0.99
DEOGEN2
Benign
0.27
T;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Uncertain
0.20
D
MutationAssessor
Pathogenic
2.9
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.42
T
PROVEAN
Pathogenic
-7.0
D;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.89
MutPred
0.89
Loss of sheet (P = 0.1158);.;
MVP
0.96
MPC
0.60
ClinPred
0.79
D
GERP RS
5.7
Varity_R
0.81
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.81
dbscSNV1_RF
Benign
0.64
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs752973900; hg19: chr11-113802107; API