7-155084416-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024012.4(HTR5A):​c.1003C>T​(p.Pro335Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

HTR5A
NM_024012.4 missense

Scores

15
3
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HTR5ANM_024012.4 linkuse as main transcriptc.1003C>T p.Pro335Ser missense_variant 2/2 ENST00000287907.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HTR5AENST00000287907.3 linkuse as main transcriptc.1003C>T p.Pro335Ser missense_variant 2/21 NM_024012.4 P1
HTR5AENST00000486819.1 linkuse as main transcriptn.359C>T non_coding_transcript_exon_variant 2/21
HTR5AENST00000649716.1 linkuse as main transcriptc.*472C>T 3_prime_UTR_variant, NMD_transcript_variant 3/3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000468
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 07, 2023The c.1003C>T (p.P335S) alteration is located in exon 2 (coding exon 2) of the HTR5A gene. This alteration results from a C to T substitution at nucleotide position 1003, causing the proline (P) at amino acid position 335 to be replaced by a serine (S). 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
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.71
D;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.6
H;H
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-7.2
D;.
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;D
Vest4
0.92
MutPred
0.87
Gain of glycosylation at P335 (P = 0.1662);Gain of glycosylation at P335 (P = 0.1662);
MVP
0.98
MPC
1.1
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.88
gMVP
0.97

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1795453169; hg19: chr7-154876126; COSMIC: COSV99839458; API