1-212100411-C-G

Position:

• chr1-212100411-C-G

Variant summary

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

The NM_016448.4(DTL):​c.1421C>G​(p.Ala474Gly) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: DTL NM_016448.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72

Genes affected

DTL (HGNC:30288): (denticleless E3 ubiquitin protein ligase homolog) Contributes to ubiquitin-protein transferase activity. Involved in several processes, including protein ubiquitination; regulation of G2/M transition of mitotic cell cycle; and translesion synthesis. Located in centrosome; cytosol; and nuclear lumen. Part of Cul4A-RING E3 ubiquitin ligase complex and Cul4B-RING E3 ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

DTL (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=0.11081451).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTL	NM_016448.4	c.1421C>G	p.Ala474Gly	missense_variant	14/15	ENST00000366991.5	NP_057532.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTL	ENST00000366991.5	c.1421C>G	p.Ala474Gly	missense_variant	14/15	1	NM_016448.4	ENSP00000355958.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 59

GnomAD4 genome Cov.: 30

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 12, 2021

The c.1421C>G (p.A474G) alteration is located in exon 14 (coding exon 14) of the DTL gene. This alteration results from a C to G substitution at nucleotide position 1421, causing the alanine (A) at amino acid position 474 to be replaced by a glycine (G). 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	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.0010	B;B
Vest4		0.15
MutPred		0.17		.;Gain of MoRF binding (P = 0.1376);
MVP		0.73
MPC		0.31
ClinPred		0.57	D
GERP RS		3.6
Varity_R		0.15
gMVP		0.23

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: rs1655582771; hg19: chr1-212273753;