Genetic Variant NM_000863.3:c.371T>G (chr6-77463033-A-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000863.3(HTR1B):c.371T>G(p.Phe124Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,614,186 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0091 ( 7 hom., cov: 32)

Exomes 𝑓: 0.013 ( 163 hom. )

Consequence

HTR1B
NM_000863.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.32

Publications

27 publications found

Variant links:

Genes affected

HTR1B (HGNC:5287): (5-hydroxytryptamine receptor 1B) The protein encoded by this intronless gene is a G-protein coupled receptor for serotonin (5-hydroxytryptamine). Ligand binding activates second messengers that inhibit the activity of adenylate cyclase and manage the release of serotonin, dopamine, and acetylcholine in the brain. The encoded protein may be involved in several neuropsychiatric disorders and therefore is often a target of antidepressant and other psychotherapeutic drugs. [provided by RefSeq, Nov 2015]

HTR1B links:

LOC105377864 (HGNC:):

LOC105377864 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012479603).

BS2

High AC in GnomAd4 at 1387 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000863.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR1B	NM_000863.3	MANE Select	c.371T>G	p.Phe124Cys	missense	Exon 1 of 1	NP_000854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR1B	ENST00000369947.5	TSL:6 MANE Select	c.371T>G	p.Phe124Cys	missense	Exon 1 of 1	ENSP00000358963.3
	ENSG00000296734	ENST00000741460.1		n.48+3867T>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00911

AC:

1386

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00706

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0143

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00994

AC:

2498

AN:

251286

AF XY:

0.00991

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00885

Gnomad ASJ exome

AF:

0.0149

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00924

Gnomad NFE exome

AF:

0.0137

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.0131

AC:

19138

AN:

1461868

Hom.:

163

Cov.:

AF XY:

0.0128

AC XY:

9305

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

33480

American (AMR)

AF:

0.00874

AC:

391

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0159

AC:

415

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00654

AC:

564

AN:

86256

European-Finnish (FIN)

AF:

0.00908

AC:

485

AN:

53398

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0148

AC:

16451

AN:

1112010

Other (OTH)

AF:

0.0122

AC:

736

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1249

2498

3748

4997

6246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

634

1268

1902

2536

3170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00911

AC:

1387

AN:

152318

Hom.:

Cov.:

AF XY:

0.00827

AC XY:

616

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41582

American (AMR)

AF:

0.0103

AC:

158

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5162

South Asian (SAS)

AF:

0.00414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00706

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0142

AC:

969

AN:

68026

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

156

233

311

389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0124

Hom.:

Bravo

AF:

0.00908

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.00925

AC:

1123

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0142

EpiControl

AF:

0.0139

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.86

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

9.3

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.6

REVEL

Benign

0.12

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.67

Vest4

0.56

MVP

0.44

MPC

1.5

ClinPred

0.033

GERP RS

5.3

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.38

gMVP

0.71

Mutation Taster

=56/44

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over