15-31483818-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001382637.1(OTUD7A):c.2278A>G(p.Ser760Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.991 in 1,003,664 control chromosomes in the GnomAD database, including 492,514 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (71836 hom., cov: 27)
  • Exomes 𝑓: 0.99 (420678 hom.)
• Consequence: OTUD7A NM_001382637.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0740

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.964613E-7).
• BP6: Variant 15-31483818-T-C is Benign according to our data. Variant chr15-31483818-T-C is described in ClinVar as [Benign]. Clinvar id is 1242878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTUD7A	NM_001382637.1	c.2278A>G	p.Ser760Gly	missense_variant	13/13	ENST00000307050.6
OTUD7A	NM_130901.3	c.2257A>G	p.Ser753Gly	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTUD7A	ENST00000307050.6	c.2278A>G	p.Ser760Gly	missense_variant	13/13	1	NM_001382637.1	P2
OTUD7A	ENST00000560598.2	c.2257A>G	p.Ser753Gly	missense_variant	14/14	5		A2
OTUD7A	ENST00000678495.1	c.2257A>G	p.Ser753Gly	missense_variant	11/11			A2

Frequencies

GnomAD3 genomes AF: 0.994 AC: 144370 AN: 145172 Hom.: 71786 Cov.: 27

Gnomad AFR AF: 0.999

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 0.997

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.991

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.997

GnomAD3 exomes AF: 0.991 AC: 212 AN: 214 Hom.: 105 AF XY: 0.984 AC XY: 120 AN XY: 122

Gnomad NFE exome AF: 0.990

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 0.990 AC: 849823 AN: 858392 Hom.: 420678 Cov.: 47 AF XY: 0.990 AC XY: 394913 AN XY: 398918

Gnomad4 AFR exome AF: 0.999

Gnomad4 AMR exome AF: 0.998

Gnomad4 ASJ exome AF: 0.996

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.994

Gnomad4 FIN exome AF: 0.990

Gnomad4 NFE exome AF: 0.990

Gnomad4 OTH exome AF: 0.992

GnomAD4 genome AF: 0.994 AC: 144470 AN: 145272 Hom.: 71836 Cov.: 27 AF XY: 0.995 AC XY: 70253 AN XY: 70624

Gnomad4 AFR AF: 0.999

Gnomad4 AMR AF: 0.997

Gnomad4 ASJ AF: 0.997

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.997

Gnomad4 FIN AF: 0.991

Gnomad4 NFE AF: 0.991

Gnomad4 OTH AF: 0.997

Alfa AF: 0.991 Hom.: 9097

Bravo AF: 0.995

TwinsUK AF: 0.997 AC: 3697

ALSPAC AF: 0.997 AC: 3842

ExAC AF: 1.00 AC: 36

Asia WGS AF: 0.997 AC: 2216 AN: 2222

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 02, 2018

- -

OTUD7A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	4.8
Dann	Benign	0.30
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.027
Sift	Benign	0.26	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.044
ClinPred		0.061	T
GERP RS		1.5
Varity_R		0.051
gMVP		0.35

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: rs2338681; hg19: chr15-31776021; COSMIC: COSV61039031;