rs6299

Variant names:

• chr1-23193426-G-A
• rs6299
• NM_000864.5:c.794C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000864.5(HTR1D):​c.794C>T​(p.Ser265Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0015 in 1,614,208 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (26 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (11 hom.)
• Consequence: HTR1D NM_000864.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.89
• Publications: 7 publications found

Genes affected

HTR1D (HGNC:5289): (5-hydroxytryptamine receptor 1D) Enables G protein-coupled serotonin receptor activity. Involved in adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway and intestine smooth muscle contraction. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032603145).
• BP6: Variant 1-23193426-G-A is Benign according to our data. Variant chr1-23193426-G-A is described in ClinVar as Benign. ClinVar VariationId is 789915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00796 (1212/152330) while in subpopulation AFR AF = 0.0274 (1139/41570). AF 95% confidence interval is 0.0261. There are 26 homozygotes in GnomAd4. There are 585 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000864.5. 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
	HTR1D	NM_000864.5	MANE Select	c.794C>T	p.Ser265Leu	missense	Exon 2 of 2	NP_000855.1	P28221

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR1D	ENST00000374619.2	TSL:6 MANE Select	c.794C>T	p.Ser265Leu	missense	Exon 2 of 2	ENSP00000363748.1	P28221
	HTR1D	ENST00000918575.1		c.794C>T	p.Ser265Leu	missense	Exon 2 of 3	ENSP00000588634.1
	HTR1D	ENST00000918576.1		c.794C>T	p.Ser265Leu	missense	Exon 2 of 2	ENSP00000588635.1

Frequencies

GnomAD3 genomes AF: 0.00795 AC: 1210 AN: 152212 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00209 AC: 526 AN: 251422 AF XY: 0.00154

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000829 AC: 1212 AN: 1461878 Hom.: 11 Cov.: 33 AF XY: 0.000689 AC XY: 501 AN XY: 727238

African (AFR) AF: 0.0300 AC: 1006 AN: 33480

American (AMR) AF: 0.00114 AC: 51 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1112000

Other (OTH) AF: 0.00171 AC: 103 AN: 60396

GnomAD4 genome AF: 0.00796 AC: 1212 AN: 152330 Hom.: 26 Cov.: 32 AF XY: 0.00785 AC XY: 585 AN XY: 74498

African (AFR) AF: 0.0274 AC: 1139 AN: 41570

American (AMR) AF: 0.00307 AC: 47 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68038

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00313 Hom.: 15

Bravo AF: 0.00924

ESP6500AA AF: 0.0293 AC: 129

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00257 AC: 312

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: 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	0.069
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.066
Sift	Benign	0.21	T
Sift4G	Benign	0.36	T
Polyphen		0.0030	B
Vest4		0.19
MVP		0.48
MPC		0.11
ClinPred		0.026	T
GERP RS		3.9
Varity_R		0.067
gMVP		0.25
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs6299; hg19: chr1-23519919;