15-31483839-C-A

Position:

• chr15-31483839-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001382637.1(OTUD7A):​c.2257G>T​(p.Gly753Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000238 in 840,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: OTUD7A NM_001382637.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.123

Genes affected

OTUD7A (HGNC:20718): (OTU deubiquitinase 7A) The protein encoded by this gene is a deubiquitinizing enzyme and possible tumor suppressor. The encoded protein acts on TNF receptor associated factor 6 (TRAF6) to control nuclear factor kappa B expression. However, this gene is downregulated by SNAIL1 in hepatocellular carcinoma cells, contributing to their progression and malignancy. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13767478).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTUD7A	NM_001382637.1	c.2257G>T	p.Gly753Trp	missense_variant	13/13	ENST00000307050.6	NP_001369566.1
OTUD7A	NM_130901.3	c.2236G>T	p.Gly746Trp	missense_variant	14/14		NP_570971.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTUD7A	ENST00000307050.6	c.2257G>T	p.Gly753Trp	missense_variant	13/13	1	NM_001382637.1	ENSP00000305926.5
OTUD7A	ENST00000560598.2	c.2236G>T	p.Gly746Trp	missense_variant	14/14	5		ENSP00000453883.2
OTUD7A	ENST00000678495.1	c.2236G>T	p.Gly746Trp	missense_variant	11/11			ENSP00000503326.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.0000238 AC: 20 AN: 840066 Hom.: 0 Cov.: 46 AF XY: 0.0000206 AC XY: 8 AN XY: 389064

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: 0.0000235

Gnomad4 OTH exome AF: 0.0000721

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

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

Oct 16, 2023

The c.2236G>T (p.G746W) alteration is located in exon 11 (coding exon 11) of the OTUD7A gene. This alteration results from a G to T substitution at nucleotide position 2236, causing the glycine (G) at amino acid position 746 to be replaced by a tryptophan (W). 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	0.29
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.056
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.98	D
Vest4		0.21
MutPred		0.23		Loss of relative solvent accessibility (P = 0.0186);
MVP		0.043
ClinPred		0.29	T
GERP RS		0.29
Varity_R		0.083
gMVP		0.41

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: rs1250031637; hg19: chr15-31776042;