ENST00000375498.6:c.12G>C

Variant names:

• chr11-113975319-G-C
• rs190646973
• ENST00000375498.6:c.12G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000375498.6(HTR3A):​c.12G>C​(p.Lys4Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign 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 Benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HTR3A ENST00000375498.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.898
• Publications: 3 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14008215).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375498.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR3A	NM_000869.6	MANE Select	c.-7G>C		5_prime_UTR	Exon 1 of 9	NP_000860.3	P46098-1
	HTR3A	NM_213621.4		c.-7G>C		5_prime_UTR	Exon 1 of 8	NP_998786.3	P46098-2
	HTR3A	NR_046363.2		n.212G>C		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR3A	ENST00000375498.6	TSL:1	c.12G>C	p.Lys4Asn	missense	Exon 1 of 9	ENSP00000364648.2	P46098-4
	HTR3A	ENST00000504030.7	TSL:1 MANE Select	c.-7G>C		5_prime_UTR	Exon 1 of 9	ENSP00000424189.2	P46098-1
	HTR3A	ENST00000355556.6	TSL:2	c.12G>C	p.Lys4Asn	missense	Exon 1 of 8	ENSP00000347754.2	P46098-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 249970 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461104 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 726834

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.96
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.87	T
PhyloP100		0.90
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.13
Sift	Benign	0.14	T
Sift4G	Benign	0.12	T
Vest4		0.29
MutPred		0.38		Loss of MoRF binding (P = 0.0145)
MVP		0.82
MPC		0.092
ClinPred		0.32	T
GERP RS		2.8
PromoterAI		0.0075	Neutral
gMVP		0.76
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs190646973; hg19: chr11-113846041;