7-155084234-C-A

Position:

• chr7-155084234-C-A

Variant summary

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

The NM_024012.4(HTR5A):​c.821C>A​(p.Thr274Lys) 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 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HTR5A NM_024012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57

Genes affected

HTR5A (HGNC:5300): (5-hydroxytryptamine receptor 5A) The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in a wide range of psychiatric conditions and also has vasoconstrictive and vasodilatory effects. The gene described in this record is a member of 5-hydroxytryptamine (serotonin) receptor family and encodes a multi-pass membrane protein that functions as a receptor for 5-hydroxytryptamine and couples to G-proteins. This protein has been shown to function in part through the regulation of intracellular Ca2+ mobilization. [provided by RefSeq, Jul 2008]

HTR5A (HGNC:):

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=0.16915324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR5A	NM_024012.4	c.821C>A	p.Thr274Lys	missense_variant	2/2	ENST00000287907.3	NP_076917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR5A	ENST00000287907.3	c.821C>A	p.Thr274Lys	missense_variant	2/2	1	NM_024012.4	ENSP00000287907.2
HTR5A	ENST00000486819.1	n.177C>A		non_coding_transcript_exon_variant	2/2	1
HTR5A	ENST00000649716.1	n.*290C>A		non_coding_transcript_exon_variant	3/3			ENSP00000497222.1
HTR5A	ENST00000649716.1	n.*290C>A		3_prime_UTR_variant	3/3			ENSP00000497222.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Jan 24, 2023

The c.821C>A (p.T274K) alteration is located in exon 2 (coding exon 2) of the HTR5A gene. This alteration results from a C to A substitution at nucleotide position 821, causing the threonine (T) at amino acid position 274 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	Benign	0.16
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.069	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.74
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.12	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.75	N;.
REVEL	Benign	0.073
Sift	Benign	0.073	T;.
Sift4G	Benign	0.49	T;.
Polyphen		0.13	B;B
Vest4		0.33
MutPred		0.44		Gain of ubiquitination at T274 (P = 0.0114);Gain of ubiquitination at T274 (P = 0.0114);
MVP		0.73
MPC		0.46
ClinPred		0.35	T
GERP RS		3.0
Varity_R		0.13
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr7-154875944;