3-8768017-G-C

Variant names:

• chr3-8768017-G-C
• rs2228485
• NM_000916.4:c.171C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000916.4(OXTR):​c.171C>G​(p.Asn57Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OXTR NM_000916.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.98
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

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.171C>G	p.Asn57Lys	missense	Exon 3 of 4	NP_000907.2
	OXTR	NM_001354653.2		c.171C>G	p.Asn57Lys	missense	Exon 4 of 5	NP_001341582.1	B2R9L7
	OXTR	NM_001354654.2		c.171C>G	p.Asn57Lys	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.171C>G	p.Asn57Lys	missense	Exon 3 of 4	ENSP00000324270.2	P30559
	OXTR	ENST00000894689.1		c.171C>G	p.Asn57Lys	missense	Exon 3 of 4	ENSP00000564748.1
	OXTR	ENST00000894690.1		c.171C>G	p.Asn57Lys	missense	Exon 3 of 4	ENSP00000564749.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453878 Hom.: 0 Cov.: 64 AF XY: 0.00000277 AC XY: 2 AN XY: 722670

African (AFR) AF: 0.00 AC: 0 AN: 33156

American (AMR) AF: 0.00 AC: 0 AN: 43862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39242

South Asian (SAS) AF: 0.00 AC: 0 AN: 85054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108774

Other (OTH) AF: 0.00 AC: 0 AN: 60064

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		5.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.90		Gain of ubiquitination at N57 (P = 0.0155)
MVP		0.96
MPC		1.7
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.99
gMVP		0.95
Mutation Taster		=22/78	disease causing

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: rs2228485; hg19: chr3-8809703;