5-63961061-C-A

Position:

• chr5-63961061-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000524.4(HTR1A):​c.659G>T​(p.Arg220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,614,228 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (36 hom.)
• Consequence: HTR1A NM_000524.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.799

Genes affected

HTR1A (HGNC:5286): (5-hydroxytryptamine receptor 1A) This gene encodes a G protein-coupled receptor for 5-hydroxytryptamine (serotonin), and belongs to the 5-hydroxytryptamine receptor subfamily. Serotonin has been implicated in a number of physiologic processes and pathologic conditions. Inactivation of this gene in mice results in behavior consistent with an increased anxiety and stress response. Mutation in the promoter of this gene has been associated with menstrual cycle-dependent periodic fevers. [provided by RefSeq, Jun 2012]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01069361).
• BP6: Variant 5-63961061-C-A is Benign according to our data. Variant chr5-63961061-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1315755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 580 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR1A	NM_000524.4	c.659G>T	p.Arg220Leu	missense_variant	1/1	ENST00000323865.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR1A	ENST00000323865.5	c.659G>T	p.Arg220Leu	missense_variant	1/1		NM_000524.4	P1
	ENST00000502882.1	n.97-3046G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 580 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00633

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00368 AC: 926 AN: 251326 Hom.: 2 AF XY: 0.00388 AC XY: 527 AN XY: 135888

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00346

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00584

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00558 AC: 8153 AN: 1461876 Hom.: 36 Cov.: 31 AF XY: 0.00541 AC XY: 3933 AN XY: 727242

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00343

Gnomad4 FIN exome AF: 0.00301

Gnomad4 NFE exome AF: 0.00640

Gnomad4 OTH exome AF: 0.00664

GnomAD4 genome AF: 0.00381 AC: 580 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.00393 AC XY: 293 AN XY: 74490

Gnomad4 AFR AF: 0.000841

Gnomad4 AMR AF: 0.00398

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00633

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00536 Hom.: 4

Bravo AF: 0.00359

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00360 AC: 437

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00573

EpiControl AF: 0.00528

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	HTR1A: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 19105200, 8645269, 20196180, 15864118) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.055
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Benign	0.11	T
Sift4G	Benign	0.29	T
Polyphen		0.76	P
Vest4		0.42
MVP		0.55
MPC		1.4
ClinPred		0.019	T
GERP RS		4.7
Varity_R		0.24
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1800044; hg19: chr5-63256888;