3-8769477-A-G

Variant names:

• chr3-8769477-A-G
• rs968389
• NM_000916.4:c.-485T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000916.4(OXTR):​c.-485T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 152,274 control chromosomes in the GnomAD database, including 16,440 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (16435 hom., cov: 35)
  • Exomes 𝑓: 0.48 (5 hom.)
• Consequence: OXTR NM_000916.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.73
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OXTR	NM_000916.4	c.-485T>C		5_prime_UTR_variant	Exon 1 of 4	ENST00000316793.8	NP_000907.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OXTR	ENST00000316793.8	c.-485T>C		5_prime_UTR_variant	Exon 1 of 4	1	NM_000916.4	ENSP00000324270.2
OXTR	ENST00000474615.1	n.137T>C		non_coding_transcript_exon_variant	Exon 1 of 2	4
OXTR	ENST00000431493.1	c.-462T>C		5_prime_UTR_variant	Exon 1 of 3	4		ENSP00000414828.1
CAV3	ENST00000472766.1	n.156-8000A>G		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70356 AN: 152098 Hom.: 16424 Cov.: 35

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.469

GnomAD4 exome AF: 0.483 AC: 28 AN: 58 Hom.: 5 Cov.: 0 AF XY: 0.479 AC XY: 23 AN XY: 48

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.519 AC: 27 AN: 52

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.463 AC: 70405 AN: 152216 Hom.: 16435 Cov.: 35 AF XY: 0.470 AC XY: 34997 AN XY: 74426

African (AFR) AF: 0.437 AC: 18151 AN: 41522

American (AMR) AF: 0.456 AC: 6978 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1494 AN: 3472

East Asian (EAS) AF: 0.655 AC: 3382 AN: 5166

South Asian (SAS) AF: 0.505 AC: 2437 AN: 4822

European-Finnish (FIN) AF: 0.549 AC: 5831 AN: 10624

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.451 AC: 30676 AN: 67982

Other (OTH) AF: 0.470 AC: 992 AN: 2112

Alfa AF: 0.297 Hom.: 696

Bravo AF: 0.456

Asia WGS AF: 0.543 AC: 1891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.53
DANN	Benign	0.37
PhyloP100		-2.7
PromoterAI		0.16	Neutral
Mutation Taster		=300/0	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: rs968389; hg19: chr3-8811163;