5-148509587-C-G

Position:

• chr5-148509587-C-G

Variant summary

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

The NM_000870.7(HTR4):​c.945G>C​(p.Leu315Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 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: HTR4 NM_000870.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

Genes affected

HTR4 (HGNC:5299): (5-hydroxytryptamine receptor 4) This gene is a member of the family of serotonin receptors, which are G protein coupled receptors that stimulate cAMP production in response to serotonin (5-hydroxytryptamine). The gene product is a glycosylated transmembrane protein that functions in both the peripheral and central nervous system to modulate the release of various neurotransmitters. Multiple transcript variants encoding proteins with distinct C-terminal sequences have been described. [provided by RefSeq, May 2010]

HTR4 (HGNC:):

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	Protein	UniProt
HTR4	NM_000870.7	c.945G>C	p.Leu315Phe	missense_variant	6/7	ENST00000377888.8	NP_000861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR4	ENST00000377888.8	c.945G>C	p.Leu315Phe	missense_variant	6/7	1	NM_000870.7	ENSP00000367120.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Dec 19, 2023

The c.945G>C (p.L315F) alteration is located in exon 5 (coding exon 5) of the HTR4 gene. This alteration results from a G to C substitution at nucleotide position 945, causing the leucine (L) at amino acid position 315 to be replaced by a phenylalanine (F). 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	0.53
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.25
DEOGEN2	Benign	0.063	.;.;.;.;T;.;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.0084
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D;D;D;D;.;.;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.33	N;N;N;N;N;N;N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	1.9	N;N;N;N;N;N;.;.
REVEL	Benign	0.21
Sift	Benign	1.0	T;T;T;T;T;T;.;.
Sift4G	Benign	0.93	T;T;T;T;T;T;T;T
Polyphen		0.38	B;.;P;.;B;.;.;B
Vest4		0.75
MutPred		0.68		Gain of ubiquitination at K317 (P = 0.1008);Gain of ubiquitination at K317 (P = 0.1008);Gain of ubiquitination at K317 (P = 0.1008);Gain of ubiquitination at K317 (P = 0.1008);Gain of ubiquitination at K317 (P = 0.1008);Gain of ubiquitination at K317 (P = 0.1008);Gain of ubiquitination at K317 (P = 0.1008);Gain of ubiquitination at K317 (P = 0.1008);
MVP		0.57
MPC		0.34
ClinPred		0.82	D
GERP RS		5.9
Varity_R		0.17
gMVP		0.79

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: chr5-147889150;