rs61740241

chr3-8767476-C-T

Variant summary

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

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (36 hom., cov: 33)
  • Exomes 𝑓: 0.028 (661 hom.)
• Consequence: OXTR NM_000916.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.42

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 -14 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 criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2977 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OXTR	NM_000916.4	c.712G>A	p.Ala238Thr	missense_variant	3/4	ENST00000316793.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OXTR	ENST00000316793.8	c.712G>A	p.Ala238Thr	missense_variant	3/4	1	NM_000916.4	P1
CAV3	ENST00000472766.1	n.156-10001C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2977 AN: 152212 Hom.: 36 Cov.: 33

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

GnomAD3 exomes AF: 0.0199 AC: 4521 AN: 226688 Hom.: 67 AF XY: 0.0201 AC XY: 2491 AN XY: 124206

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 SAS exome AF: 0.00527

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.: 30 AF XY: 0.0270 AC XY: 19507 AN XY: 721884

Gnomad4 AFR exome AF: 0.00452

Gnomad4 AMR exome AF: 0.0173

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00546

Gnomad4 FIN exome AF: 0.0161

Gnomad4 NFE exome AF: 0.0330

Gnomad4 OTH exome AF: 0.0220

GnomAD4 genome AF: 0.0195 AC: 2976 AN: 152322 Hom.: 36 Cov.: 33 AF XY: 0.0188 AC XY: 1397 AN XY: 74488

Gnomad4 AFR AF: 0.00548

Gnomad4 AMR AF: 0.0292

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.0297

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0266 Hom.: 25

Bravo AF: 0.0212

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0322 AC: 124

ESP6500AA AF: 0.00776 AC: 34

ESP6500EA AF: 0.0262 AC: 225

ExAC AF: 0.0192 AC: 2328

Asia WGS AF: 0.00260 AC: 9 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

OXTR-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2020

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	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	16
Dann	Benign	0.85
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.67	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.12
Sift	Benign	0.54	T
Sift4G	Benign	0.57	T
Polyphen		0.0020	B
Vest4		0.046
MPC		0.63
ClinPred		0.014	T
GERP RS		5.3
Varity_R		0.21
gMVP		0.80

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: rs61740241; hg19: chr3-8809162; COSMIC: COSV57480187; COSMIC: COSV57480187;