1-212100411-C-G

Variant names:

• chr1-212100411-C-G
• rs1655582771
• NM_016448.4:c.1421C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 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
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11081451).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016448.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTL	NM_016448.4	MANE Select	c.1421C>G	p.Ala474Gly	missense	Exon 14 of 15	NP_057532.4	Q9NZJ0-1
	DTL	NM_001286230.2		c.1295C>G	p.Ala432Gly	missense	Exon 13 of 14	NP_001273159.2	F5GZ90
	DTL	NM_001286229.2		c.608C>G	p.Ala203Gly	missense	Exon 12 of 13	NP_001273158.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTL	ENST00000366991.5	TSL:1 MANE Select	c.1421C>G	p.Ala474Gly	missense	Exon 14 of 15	ENSP00000355958.4	Q9NZJ0-1
	DTL	ENST00000935628.1		c.1469C>G	p.Ala490Gly	missense	Exon 15 of 16	ENSP00000605687.1
	DTL	ENST00000935625.1		c.1418C>G	p.Ala473Gly	missense	Exon 14 of 15	ENSP00000605684.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 59

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.11
Sift	Uncertain	0.027	D
Sift4G	Benign	0.13	T
Polyphen		0.0010	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
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1655582771; hg19: chr1-212273753;