chr11-59182107-T-C

Position:

• chr11-59182107-T-C

Variant summary

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

The NM_015177.2(DTX4):​c.580T>C​(p.Cys194Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DTX4 NM_015177.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

Genes affected

DTX4 (HGNC:29151): (deltex E3 ubiquitin ligase 4) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in Notch signaling pathway and protein ubiquitination. Predicted to be located in cytosol. Predicted to be active in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

LOC124902675 (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=0.3926081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTX4	NM_015177.2	c.580T>C	p.Cys194Arg	missense_variant	2/9	ENST00000227451.4	NP_055992.1
DTX4	NM_001300727.2	c.262T>C	p.Cys88Arg	missense_variant	2/9		NP_001287656.1
LOC124902675	XR_007062681.1	n.2649-2288A>G		intron_variant
LOC124902675	XR_007062682.1	n.2649-2288A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTX4	ENST00000227451.4	c.580T>C	p.Cys194Arg	missense_variant	2/9	1	NM_015177.2	ENSP00000227451.3
DTX4	ENST00000532982.5	c.262T>C	p.Cys88Arg	missense_variant	2/9	1		ENSP00000434055.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

May 18, 2023

The c.580T>C (p.C194R) alteration is located in exon 2 (coding exon 2) of the DTX4 gene. This alteration results from a T to C substitution at nucleotide position 580, causing the cysteine (C) at amino acid position 194 to be replaced by an arginine (R). 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	Pathogenic	1.0
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	.;T
Eigen	Benign	-0.017
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.0020	.;B
Vest4		0.65
MutPred		0.46		.;Loss of sheet (P = 7e-04);
MVP		0.39
MPC		1.2
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.95
gMVP		0.79

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: rs1862471608; hg19: chr11-58949580;