3-8767536-C-T

Variant names:

• chr3-8767536-C-T
• rs4686302
• NM_000916.4:c.652G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 80 publications found

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]

CAV3 Gene-Disease associations (from GenCC):

• caveolinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant limb-girdle muscular dystrophy type 1C

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• long QT syndrome 9

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• rippling muscle disease 2

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• distal myopathy, Tateyama type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• inherited rippling muscle disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• long QT syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
OXTR	NM_000916.4	c.652G>A	p.Ala218Thr	missense_variant	Exon 3 of 4	ENST00000316793.8	NP_000907.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OXTR	ENST00000316793.8	c.652G>A	p.Ala218Thr	missense_variant	Exon 3 of 4	1	NM_000916.4	ENSP00000324270.2
CAV3	ENST00000472766.1	n.156-9941C>T		intron_variant	Intron 1 of 2	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

GnomAD2 exomes AF: 0.153 AC: 37849 AN: 246624 AF XY: 0.146

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 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

African (AFR) AF: 0.0702 AC: 2349 AN: 33446

American (AMR) AF: 0.317 AC: 14130 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2964 AN: 26102

East Asian (EAS) AF: 0.213 AC: 8452 AN: 39640

South Asian (SAS) AF: 0.139 AC: 11988 AN: 86220

European-Finnish (FIN) AF: 0.130 AC: 6891 AN: 52960

Middle Eastern (MID) AF: 0.107 AC: 617 AN: 5766

European-Non Finnish (NFE) AF: 0.115 AC: 127876 AN: 1111588

Other (OTH) AF: 0.123 AC: 7394 AN: 60340

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

African (AFR) AF: 0.0728 AC: 3027 AN: 41560

American (AMR) AF: 0.221 AC: 3389 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3472

East Asian (EAS) AF: 0.186 AC: 959 AN: 5160

South Asian (SAS) AF: 0.143 AC: 688 AN: 4828

European-Finnish (FIN) AF: 0.124 AC: 1321 AN: 10614

Middle Eastern (MID) AF: 0.0925 AC: 27 AN: 292

European-Non Finnish (NFE) AF: 0.119 AC: 8106 AN: 68002

Other (OTH) AF: 0.121 AC: 256 AN: 2110

Alfa AF: 0.124 Hom.: 2509

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 29, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.45
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
Mutation Taster		=95/5	polymorphism (auto)

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