20-3072099-G-A

Position:

• chr20-3072099-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000915.4(OXT):​c.143G>A​(p.Gly48Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,395,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: OXT NM_000915.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96

Genes affected

OXT (HGNC:8528): (oxytocin/neurophysin I prepropeptide) This gene encodes a precursor protein that is processed to produce oxytocin and neurophysin I. Oxytocin is a posterior pituitary hormone which is synthesized as an inactive precursor in the hypothalamus along with its carrier protein neurophysin I. Together with neurophysin, it is packaged into neurosecretory vesicles and transported axonally to the nerve endings in the neurohypophysis, where it is either stored or secreted into the bloodstream. The precursor seems to be activated while it is being transported along the axon to the posterior pituitary. This hormone contracts smooth muscle during parturition and lactation. It is also involved in cognition, tolerance, adaptation and complex sexual and maternal behaviour, as well as in the regulation of water excretion and cardiovascular functions. [provided by RefSeq, Dec 2013]

LOC101929098 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3111866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OXT	NM_000915.4	c.143G>A	p.Gly48Asp	missense_variant	2/3	ENST00000217386.2	NP_000906.1
LOC101929098	XR_430278.4	n.103+98C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OXT	ENST00000217386.2	c.143G>A	p.Gly48Asp	missense_variant	2/3	1	NM_000915.4	ENSP00000217386	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000358 AC: 5 AN: 1395340 Hom.: 0 Cov.: 32 AF XY: 0.00000289 AC XY: 2 AN XY: 690852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000460

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2022

The c.143G>A (p.G48D) alteration is located in exon 2 (coding exon 2) of the OXT gene. This alteration results from a G to A substitution at nucleotide position 143, causing the glycine (G) at amino acid position 48 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.086
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.092	D
MutationAssessor	Benign	0.41	N
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.24
Sift	Benign	0.67	T
Sift4G	Benign	0.77	T
Polyphen		0.022	B
Vest4		0.21
MutPred		0.38		Gain of solvent accessibility (P = 0.0354);
MVP		0.51
MPC		0.56
ClinPred		0.60	D
GERP RS		4.6
Varity_R		0.095
gMVP		0.59

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: rs370932402; hg19: chr20-3052745;