5-63960902-C-T

Position:

• chr5-63960902-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000524.4(HTR1A):​c.818G>A​(p.Gly273Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,613,952 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: HTR1A NM_000524.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.405

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]

ENSG00000248285 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047688484).
• BP6: Variant 5-63960902-C-T is Benign according to our data. Variant chr5-63960902-C-T is described in ClinVar as [Benign]. Clinvar id is 779885.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000886 (135/152334) while in subpopulation EAS AF= 0.0181 (93/5130). AF 95% confidence interval is 0.0152. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 135 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR1A	NM_000524.4	c.818G>A	p.Gly273Asp	missense_variant	1/1	ENST00000323865.5	NP_000515.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR1A	ENST00000323865.5	c.818G>A	p.Gly273Asp	missense_variant	1/1	6	NM_000524.4	ENSP00000316244.4
ENSG00000248285	ENST00000502882.1	n.97-2887G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.0181

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00144 AC: 361 AN: 250992 Hom.: 4 AF XY: 0.00137 AC XY: 186 AN XY: 135746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0156

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00108 AC: 1580 AN: 1461618 Hom.: 27 Cov.: 31 AF XY: 0.00106 AC XY: 771 AN XY: 727078

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.0284

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000265

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.000886 AC: 135 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000886 AC XY: 66 AN XY: 74474

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.0181

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000267 Hom.: 0

Bravo AF: 0.000771

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00156 AC: 189

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.8
DANN	Benign	0.72
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.78	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.24
Sift	Benign	0.43	T
Sift4G	Benign	0.24	T
Polyphen		0.93	P
Vest4		0.32
MVP		0.79
MPC		1.1
ClinPred		0.042	T
GERP RS		4.3
Varity_R		0.079
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800042; hg19: chr5-63256729;