11-113977919-C-A

Position:

• chr11-113977919-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000869.6(HTR3A):​c.216C>A​(p.Asn72Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HTR3A NM_000869.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.67

Genes affected

HTR3A (HGNC:5297): (5-hydroxytryptamine receptor 3A) The product of this gene belongs to the ligand-gated ion channel receptor superfamily. This gene encodes subunit A 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 appears that the heteromeric combination of A and B subunits is necessary to provide the full functional features of this receptor, since either subunit alone results in receptors with very low conductance and response amplitude. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20831874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR3A	NM_000869.6	c.216C>A	p.Asn72Lys	missense_variant	2/9	ENST00000504030.7
HTR3A	NM_213621.4	c.216C>A	p.Asn72Lys	missense_variant	2/8
HTR3A	NM_001161772.3	c.171C>A	p.Asn57Lys	missense_variant	2/9
HTR3A	NR_046363.2	n.434C>A		non_coding_transcript_exon_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR3A	ENST00000504030.7	c.216C>A	p.Asn72Lys	missense_variant	2/9	1	NM_000869.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2023

The c.234C>A (p.N78K) alteration is located in exon 2 (coding exon 2) of the HTR3A gene. This alteration results from a C to A substitution at nucleotide position 234, causing the asparagine (N) at amino acid position 78 to be replaced by a lysine (K). 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.017
DANN	Benign	0.77
DEOGEN2	Uncertain	0.43	T;.;.;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.72	T;T;T;T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.0	L;.;.;L;.
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.078	T;T;T;T;T
Sift4G	Benign	0.087	T;T;T;T;T
Vest4		0.22
MutPred		0.63		.;Gain of ubiquitination at N78 (P = 0.0408);Gain of ubiquitination at N78 (P = 0.0408);.;.;
MVP		0.24
MPC		0.13
ClinPred		0.31	T
GERP RS		-8.9
Varity_R		0.076
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-113848641;