rs130060

Positions:

• chr6-77463033-A-C
• chr6-77463033-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0091 (7 hom., cov: 32)
  • Exomes 𝑓: 0.013 (163 hom.)
• Consequence: HTR1B NM_000863.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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]

LOC105377864 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012479603).
• BS2: High AC in GnomAd4 at 1387 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR1B	NM_000863.3	c.371T>G	p.Phe124Cys	missense_variant	1/1	ENST00000369947.5	NP_000854.1
LOC105377864	XM_047419660.1	c.-3742-11493A>C		intron_variant			XP_047275616.1
LOC105377864	XM_047419659.1	c.-11426A>C		5_prime_UTR_variant	2/6		XP_047275615.1
LOC105377864	XM_047419661.1	c.-4002A>C		5_prime_UTR_variant	1/6		XP_047275617.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR1B	ENST00000369947.5	c.371T>G	p.Phe124Cys	missense_variant	1/1		NM_000863.3	ENSP00000358963	P1

Frequencies

GnomAD3 genomes AF: 0.00911 AC: 1386 AN: 152200 Hom.: 7 Cov.: 32

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

GnomAD3 exomes AF: 0.00994 AC: 2498 AN: 251286 Hom.: 18 AF XY: 0.00991 AC XY: 1346 AN XY: 135818

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 SAS exome AF: 0.00575

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.: 38 AF XY: 0.0128 AC XY: 9305 AN XY: 727236

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00874

Gnomad4 ASJ exome AF: 0.0159

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00654

Gnomad4 FIN exome AF: 0.00908

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.00911 AC: 1387 AN: 152318 Hom.: 7 Cov.: 32 AF XY: 0.00827 AC XY: 616 AN XY: 74484

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00706

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0130 Hom.: 32

Bravo AF: 0.00908

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.00925 AC: 1123

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0139

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.67	P
Vest4		0.56
MVP		0.44
MPC		1.5
ClinPred		0.033	T
GERP RS		5.3
Varity_R		0.38
gMVP		0.71

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

Other links and lift over

dbSNP: rs130060; hg19: chr6-78172750; COSMIC: COSV105286209;