3-8767481-G-T

Variant names:

• chr3-8767481-G-T
• rs762072495
• NM_000916.4:c.707C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000916.4(OXTR):​c.707C>A​(p.Ala236Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000825 in 1,454,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A236T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: OXTR NM_000916.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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
• long QT syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36447218).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000916.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OXTR	NM_000916.4	MANE Select	c.707C>A	p.Ala236Asp	missense	Exon 3 of 4	NP_000907.2
	OXTR	NM_001354653.2		c.707C>A	p.Ala236Asp	missense	Exon 4 of 5	NP_001341582.1	B2R9L7
	OXTR	NM_001354654.2		c.707C>A	p.Ala236Asp	missense	Exon 3 of 4	NP_001341583.1	P30559

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OXTR	ENST00000316793.8	TSL:1 MANE Select	c.707C>A	p.Ala236Asp	missense	Exon 3 of 4	ENSP00000324270.2	P30559
	OXTR	ENST00000894689.1		c.707C>A	p.Ala236Asp	missense	Exon 3 of 4	ENSP00000564748.1
	OXTR	ENST00000894690.1		c.707C>A	p.Ala236Asp	missense	Exon 3 of 4	ENSP00000564749.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000867 AC: 2 AN: 230706 AF XY: 0.00000793

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000199

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000825 AC: 12 AN: 1454450 Hom.: 0 Cov.: 30 AF XY: 0.00000830 AC XY: 6 AN XY: 722960

African (AFR) AF: 0.00 AC: 0 AN: 33258

American (AMR) AF: 0.00 AC: 0 AN: 43690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 85556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000902 AC: 10 AN: 1108662

Other (OTH) AF: 0.0000333 AC: 2 AN: 60054

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.22
Sift	Benign	0.21	T
Sift4G	Benign	0.58	T
Polyphen		0.80	P
Vest4		0.34
MutPred		0.51		Gain of solvent accessibility (P = 0.0202)
MVP		0.70
MPC		0.91
ClinPred		0.31	T
GERP RS		4.4
Varity_R		0.35
gMVP		0.87
Mutation Taster		=78/22	polymorphism

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: rs762072495; hg19: chr3-8809167;