5-148548816-C-T

Position:

• chr5-148548816-C-T

Variant summary

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

The NM_000870.7(HTR4):​c.205G>A​(p.Val69Ile) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: HTR4 NM_000870.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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]

LOC107986462 (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	UniProt
HTR4	NM_000870.7	c.205G>A	p.Val69Ile	missense_variant	4/7	ENST00000377888.8
LOC107986462	XR_001742935.2	n.442-1269C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR4	ENST00000377888.8	c.205G>A	p.Val69Ile	missense_variant	4/7	1	NM_000870.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Jun 11, 2021

The c.205G>A (p.V69I) alteration is located in exon 3 (coding exon 3) of the HTR4 gene. This alteration results from a G to A substitution at nucleotide position 205, causing the valine (V) at amino acid position 69 to be replaced by an isoleucine (I). 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	0.50
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;.;.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.76	N;N;N;N;N;N;N;.
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T
Polyphen		1.0	D;.;D;.;D;.;.;D
Vest4		0.80
MutPred		0.57		Loss of catalytic residue at V69 (P = 0.1369);Loss of catalytic residue at V69 (P = 0.1369);Loss of catalytic residue at V69 (P = 0.1369);Loss of catalytic residue at V69 (P = 0.1369);Loss of catalytic residue at V69 (P = 0.1369);Loss of catalytic residue at V69 (P = 0.1369);Loss of catalytic residue at V69 (P = 0.1369);Loss of catalytic residue at V69 (P = 0.1369);
MVP		0.49
MPC		0.73
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.48
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr5-147928379;