NM_001366057.1:c.3128A>G

Variant names:

• chr4-145137647-T-C
• rs1750344446
• NM_001366057.1:c.3128A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001366057.1(OTUD4):​c.3128A>G​(p.Tyr1043Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: OTUD4 NM_001366057.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.44

Genes affected

OTUD4 (HGNC:24949): (OTU deubiquitinase 4) Alternatively spliced transcript variants have been found for this gene. The smaller protein isoform encoded by the shorter transcript variant is found only in HIV-1 infected cells. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTUD4	NM_001366057.1	c.3128A>G	p.Tyr1043Cys	missense_variant	Exon 21 of 21	ENST00000447906.8	NP_001352986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTUD4	ENST00000447906.8	c.3128A>G	p.Tyr1043Cys	missense_variant	Exon 21 of 21	5	NM_001366057.1	ENSP00000395487.2
OTUD4	ENST00000454497.6	c.2933A>G	p.Tyr978Cys	missense_variant	Exon 21 of 21	2		ENSP00000409279.2
OTUD4	ENST00000455611.6	n.2028+2304A>G		intron_variant	Intron 20 of 21	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461632 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727128

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2933A>G (p.Y978C) alteration is located in exon 21 (coding exon 20) of the OTUD4 gene. This alteration results from a A to G substitution at nucleotide position 2933, causing the tyrosine (Y) at amino acid position 978 to be replaced by a cysteine (C). 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	0.28
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.97	.;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.78
MVP		0.69
MPC		0.98
ClinPred		0.86	D
GERP RS		6.2
Varity_R		0.48
gMVP		0.11

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: rs1750344446; hg19: chr4-146058799;