3-8767476-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000916.4(OXTR):c.712G>A(p.Ala238Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.027 in 1,604,954 control chromosomes in the GnomAD database, including 697 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A238G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 36 hom., cov: 33)

Exomes 𝑓: 0.028 ( 661 hom. )

Consequence

OXTR
NM_000916.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.42

Publications

10 publications found

Variant links:

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]

OXTR links:

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

CAV3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002678454).

BP6

Variant 3-8767476-C-T is Benign according to our data. Variant chr3-8767476-C-T is described in ClinVar as [Benign]. Clinvar id is 3037365.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0195 (2976/152322) while in subpopulation NFE AF = 0.0297 (2023/68008). AF 95% confidence interval is 0.0287. There are 36 homozygotes in GnomAd4. There are 1397 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2976 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OXTR	NM_000916.4 link	c.712G>A	p.Ala238Thr	missense_variant	Exon 3 of 4	ENST00000316793.8	NP_000907.2	P30559B2R9L7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OXTR	ENST00000316793.8 link	c.712G>A	p.Ala238Thr	missense_variant	Exon 3 of 4	1	NM_000916.4	ENSP00000324270.2		P30559
CAV3	ENST00000472766.1 link	n.156-10001C>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0196

AC:

2977

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00550

Gnomad AMI

AF:

0.0209

Gnomad AMR

AF:

0.0292

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00558

Gnomad FIN

AF:

0.0130

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0298

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0199

AC:

4521

AN:

226688

AF XY:

0.0201

show subpopulations

Gnomad AFR exome

AF:

0.00550

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.00988

Gnomad EAS exome

AF:

0.0000591

Gnomad FIN exome

AF:

0.0155

Gnomad NFE exome

AF:

0.0325

Gnomad OTH exome

AF:

0.0228

GnomAD4 exome

AF:

0.0278

AC:

40344

AN:

1452632

Hom.:

661

Cov.:

AF XY:

0.0270

AC XY:

19507

AN XY:

721884

show subpopulations

African (AFR)

AF:

0.00452

AC:

150

AN:

33214

American (AMR)

AF:

0.0173

AC:

751

AN:

43408

Ashkenazi Jewish (ASJ)

AF:

0.0105

AC:

271

AN:

25904

East Asian (EAS)

AF:

0.00

AC:

AN:

39364

South Asian (SAS)

AF:

0.00546

AC:

466

AN:

85424

European-Finnish (FIN)

AF:

0.0161

AC:

833

AN:

51862

Middle Eastern (MID)

AF:

0.00590

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0330

AC:

36518

AN:

1107722

Other (OTH)

AF:

0.0220

AC:

1321

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

2334

4668

7002

9336

11670

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0195

AC:

2976

AN:

152322

Hom.:

Cov.:

AF XY:

0.0188

AC XY:

1397

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00548

AC:

228

AN:

41586

American (AMR)

AF:

0.0292

AC:

447

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00559

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0130

AC:

138

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0297

AC:

2023

AN:

68008

Other (OTH)

AF:

0.0237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

158

316

475

633

791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0247

Hom.:

Bravo

AF:

0.0212

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0322

AC:

124

ESP6500AA

AF:

0.00776

AC:

ESP6500EA

AF:

0.0262

AC:

225

ExAC

AF:

0.0192

AC:

2328

Asia WGS

AF:

0.00260

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

OXTR-related disorder

Benign:1

Feb 11, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.047

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.67

PhyloP100

1.4

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.030

REVEL

Benign

0.12

Sift

Benign

0.54

Sift4G

Benign

0.57

Polyphen

0.0020

Vest4

0.046

MPC

0.63

ClinPred

0.014

GERP RS

5.3

Varity_R

0.21

gMVP

0.80

Mutation Taster

=84/16

polymorphism (auto)

(source)

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

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3-8767476-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over