11-59181822-A-C

Position:

• chr11-59181822-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015177.2(DTX4):​c.295A>C​(p.Asn99His) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DTX4 NM_015177.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.349

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2415235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTX4	NM_015177.2	c.295A>C	p.Asn99His	missense_variant	2/9	ENST00000227451.4	NP_055992.1
LOC124902675	XR_007062682.1	n.2649-2003T>G		intron_variant, non_coding_transcript_variant
DTX4	NM_001300727.2	c.-24A>C		5_prime_UTR_variant	2/9		NP_001287656.1
LOC124902675	XR_007062681.1	n.2649-2003T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTX4	ENST00000227451.4	c.295A>C	p.Asn99His	missense_variant	2/9	1	NM_015177.2	ENSP00000227451	P1
DTX4	ENST00000532982.5	c.-24A>C		5_prime_UTR_variant	2/9	1		ENSP00000434055

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Apr 17, 2023

The c.295A>C (p.N99H) alteration is located in exon 2 (coding exon 2) of the DTX4 gene. This alteration results from a A to C substitution at nucleotide position 295, causing the asparagine (N) at amino acid position 99 to be replaced by a histidine (H). 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	0.069
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.052
Sift	Benign	0.056	T
Sift4G	Benign	0.14	T
Polyphen		0.60	P
Vest4		0.21
MutPred		0.47		Gain of phosphorylation at T103 (P = 0.2029);
MVP		0.74
MPC		0.36
ClinPred		0.27	T
GERP RS		3.6
Varity_R		0.089
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-58949295;