11-59181829-C-G

Position:

• chr11-59181829-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_015177.2(DTX4):​c.302C>G​(p.Ser101Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DTX4 NM_015177.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTX4	NM_015177.2	c.302C>G	p.Ser101Cys	missense_variant	2/9	ENST00000227451.4	NP_055992.1
LOC124902675	XR_007062682.1	n.2649-2010G>C		intron_variant, non_coding_transcript_variant
DTX4	NM_001300727.2	c.-17C>G		5_prime_UTR_variant	2/9		NP_001287656.1
LOC124902675	XR_007062681.1	n.2649-2010G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTX4	ENST00000227451.4	c.302C>G	p.Ser101Cys	missense_variant	2/9	1	NM_015177.2	ENSP00000227451	P1
DTX4	ENST00000532982.5	c.-17C>G		5_prime_UTR_variant	2/9	1		ENSP00000434055

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727144

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

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

Nov 21, 2022

The c.302C>G (p.S101C) alteration is located in exon 2 (coding exon 2) of the DTX4 gene. This alteration results from a C to G substitution at nucleotide position 302, causing the serine (S) at amino acid position 101 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	0.070
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.89	D;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Benign	0.087	T
Sift4G	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.62
MutPred		0.57		Loss of disorder (P = 0.0332);
MVP		0.57
MPC		0.37
ClinPred		0.61	D
GERP RS		4.7
Varity_R		0.14
gMVP		0.55

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: rs746807888; hg19: chr11-58949302;