Genetic Variant HTR3A:c.-25C>T (chr11-113975301-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000869.6(HTR3A):c.-25C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,612,804 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

HTR3A
NM_000869.6 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.496

Variant links:

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]

HTR3A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 11-113975301-C-T is Benign according to our data. Variant chr11-113975301-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HTR3A	NM_000869.6 link	c.-25C>T	5_prime_UTR_variant	Exon 1 of 9	ENST00000504030.7	NP_000860.3	P46098-1B4E398
HTR3A	NM_213621.4 link	c.-25C>T	5_prime_UTR_variant	Exon 1 of 8		NP_998786.3	P46098-2B4E398
HTR3A	NR_046363.2 link	n.194C>T	non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTR3A	ENST00000504030.7 link	c.-25C>T		5_prime_UTR_variant	Exon 1 of 9	1	NM_000869.6	ENSP00000424189.2		P46098-1

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000818

AC:

204

AN:

249390

AF XY:

0.000816

show subpopulations

Gnomad AFR exome

AF:

0.000495

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000289

Gnomad NFE exome

AF:

0.00164

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.00140

AC:

2041

AN:

1460458

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

972

AN XY:

726504

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33474

American (AMR)

AF:

0.0000671

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86138

European-Finnish (FIN)

AF:

0.000552

AC:

AN:

52522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00176

AC:

1959

AN:

1111682

Other (OTH)

AF:

0.000679

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

184

277

369

461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000794

AC:

121

AN:

152346

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41590

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00156

AC:

106

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000982

Hom.:

Bravo

AF:

0.000714

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.00166

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

8.1

(source)

DANN

Benign

0.91

PhyloP100

0.50

PromoterAI

-0.018

Neutral

(source)

Splicing

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

Publications

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chr11-113975301-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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