7-155071583-G-T

Variant summary

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

The NM_024012.4(HTR5A):c.684G>T(p.Lys228Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HTR5A NM_024012.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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-AS1 (HGNC:48956): (HTR5A antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR5A	NM_024012.4	c.684G>T	p.Lys228Asn	missense_variant	1/2	ENST00000287907.3
HTR5A-AS1	NR_038945.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR5A	ENST00000287907.3	c.684G>T	p.Lys228Asn	missense_variant	1/2	1	NM_024012.4	P1
HTR5A-AS1	ENST00000671665.1	n.868C>A		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

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

Aug 02, 2022

The c.684G>T (p.K228N) alteration is located in exon 1 (coding exon 1) of the HTR5A gene. This alteration results from a G to T substitution at nucleotide position 684, causing the lysine (K) at amino acid position 228 to be replaced by an asparagine (N). 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	0.54
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.18
Sift	Benign	0.074	T;.
Sift4G	Uncertain	0.027	D;.
Polyphen		0.29	B;B
Vest4		0.58
MutPred		0.76		Loss of methylation at K228 (P = 0.0029);Loss of methylation at K228 (P = 0.0029);
MVP		0.67
MPC		0.52
ClinPred		0.90	D
GERP RS		2.0
Varity_R		0.30
gMVP		0.76

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

LitVar

Other links and lift over

dbSNP: rs1795295906; hg19: chr7-154863293;