rs1800044

Variant names:

• chr5-63961061-C-A
• rs1800044
• NM_000524.4:c.659G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-63961061-C-A
• chr5-63961061-C-G
• chr5-63961061-C-T

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• 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
• Publications: 30 publications found

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]

HTR1A Gene-Disease associations (from GenCC):

• menstrual cycle-dependent periodic fever

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000248285 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 1315755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 580 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000524.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR1A	NM_000524.4	MANE Select	c.659G>T	p.Arg220Leu	missense	Exon 1 of 1	NP_000515.2	P08908

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR1A	ENST00000323865.5	TSL:6 MANE Select	c.659G>T	p.Arg220Leu	missense	Exon 1 of 1	ENSP00000316244.4	P08908
	ENSG00000248285	ENST00000502882.1	TSL:2	n.97-3046G>T		intron	N/A

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

GnomAD2 exomes AF: 0.00368 AC: 926 AN: 251326 AF XY: 0.00388

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 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

African (AFR) AF: 0.00105 AC: 35 AN: 33480

American (AMR) AF: 0.00154 AC: 69 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00343 AC: 296 AN: 86258

European-Finnish (FIN) AF: 0.00301 AC: 161 AN: 53402

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.00640 AC: 7114 AN: 1112012

Other (OTH) AF: 0.00664 AC: 401 AN: 60396

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

African (AFR) AF: 0.000841 AC: 35 AN: 41596

American (AMR) AF: 0.00398 AC: 61 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4820

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00633 AC: 431 AN: 68038

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00502 Hom.: 7

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.80
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
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs1800044; hg19: chr5-63256888;