rs4686302

Positions:

• chr3-8767536-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000916.4(OXTR):​c.652G>A​(p.Ala218Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,612,932 control chromosomes in the GnomAD database, including 14,096 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.12 (1300 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12796 hom.)
• Consequence: OXTR NM_000916.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.449

Genes affected

OXTR (HGNC:8529): (oxytocin receptor) The protein encoded by this gene belongs to the G-protein coupled receptor family and acts as a receptor for oxytocin. Its activity is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. The oxytocin-oxytocin receptor system plays an important role in the uterus during parturition. [provided by RefSeq, Jul 2008]

CAV3 (HGNC:1529): (caveolin 3) This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules. Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), hyperCKemia or rippling muscle disease (RMD). Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035479069).
• BP6: Variant 3-8767536-C-T is Benign according to our data. Variant chr3-8767536-C-T is described in ClinVar as [Benign]. Clinvar id is 1221201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OXTR	NM_000916.4	c.652G>A	p.Ala218Thr	missense_variant	3/4	ENST00000316793.8	NP_000907.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OXTR	ENST00000316793.8	c.652G>A	p.Ala218Thr	missense_variant	3/4	1	NM_000916.4	ENSP00000324270	P1
CAV3	ENST00000472766.1	n.156-9941C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18322 AN: 152140 Hom.: 1291 Cov.: 33

Gnomad AFR AF: 0.0725

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.153 AC: 37849 AN: 246624 Hom.: 3665 AF XY: 0.146 AC XY: 19546 AN XY: 133984

Gnomad AFR exome AF: 0.0722

Gnomad AMR exome AF: 0.327

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.182

Gnomad SAS exome AF: 0.137

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.125 AC: 182661 AN: 1460680 Hom.: 12796 Cov.: 65 AF XY: 0.125 AC XY: 90615 AN XY: 726712

Gnomad4 AFR exome AF: 0.0702

Gnomad4 AMR exome AF: 0.317

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.115

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.121 AC: 18354 AN: 152252 Hom.: 1300 Cov.: 33 AF XY: 0.124 AC XY: 9191 AN XY: 74420

Gnomad4 AFR AF: 0.0728

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.121

Alfa AF: 0.123 Hom.: 1736

Bravo AF: 0.128

TwinsUK AF: 0.121 AC: 448

ALSPAC AF: 0.112 AC: 430

ESP6500AA AF: 0.0719 AC: 317

ESP6500EA AF: 0.120 AC: 1033

ExAC AF: 0.145 AC: 17625

Asia WGS AF: 0.183 AC: 632 AN: 3472

EpiCase AF: 0.117

EpiControl AF: 0.119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2020	This variant is associated with the following publications: (PMID: 23889750) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.15	N
MutationTaster	Benign	0.89	P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.013
Sift	Benign	1.0	T
Sift4G	Benign	0.45	T
Polyphen		0.0020	B
Vest4		0.019
MPC		0.61
ClinPred		0.0079	T
GERP RS		3.5
Varity_R		0.072
gMVP		0.72

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: rs4686302; hg19: chr3-8809222; COSMIC: COSV57478240; COSMIC: COSV57478240;