1-212100487-G-A

Position:

• chr1-212100487-G-A

Variant summary

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

The NM_016448.4(DTL):​c.1497G>A​(p.Met499Ile) 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: 31)
• Consequence: DTL NM_016448.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

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=0.11751419).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTL	NM_016448.4	c.1497G>A	p.Met499Ile	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.1497G>A	p.Met499Ile	missense_variant	14/15	1	NM_016448.4	ENSP00000355958.4
DTL	ENST00000542077.5	c.1371G>A	p.Met457Ile	missense_variant	13/14	2		ENSP00000443870.1
DTL	ENST00000475419.5	n.1312G>A		non_coding_transcript_exon_variant	12/13	2
DTL	ENST00000489149.1	n.602G>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 59

GnomAD4 genome Cov.: 31

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

Dec 13, 2023

The c.1497G>A (p.M499I) alteration is located in exon 14 (coding exon 14) of the DTL gene. This alteration results from a G to A substitution at nucleotide position 1497, causing the methionine (M) at amino acid position 499 to be replaced by an isoleucine (I). 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	0.24
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.14	.;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.0	.;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.058
Sift	Benign	0.23	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.0040	B;B
Vest4		0.31
MutPred		0.36		.;Gain of methylation at K498 (P = 0.0285);
MVP		0.72
MPC		0.35
ClinPred		0.38	T
GERP RS		2.7
Varity_R		0.084
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: chr1-212273829;