4-100188073-C-A

Position:

• chr4-100188073-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145244.4(DDIT4L):​c.186G>T​(p.Glu62Asp) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DDIT4L NM_145244.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

Genes affected

DDIT4L (HGNC:30555): (DNA damage inducible transcript 4 like) Predicted to be involved in negative regulation of signal transduction. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

H2AZ1-DT (HGNC:40271): (H2AZ1 divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2709633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDIT4L	NM_145244.4	c.186G>T	p.Glu62Asp	missense_variant	3/3	ENST00000273990.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDIT4L	ENST00000273990.6	c.186G>T	p.Glu62Asp	missense_variant	3/3	1	NM_145244.4	P1
H2AZ1-DT	ENST00000515026.1	n.730-6992C>A		intron_variant, non_coding_transcript_variant		5
DDIT4L	ENST00000502763.1	c.186G>T	p.Glu62Asp	missense_variant	2/2	2
DDIT4L	ENST00000513992.1	c.186G>T	p.Glu62Asp	missense_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Oct 10, 2023

The c.186G>T (p.E62D) alteration is located in exon 3 (coding exon 2) of the DDIT4L gene. This alteration results from a G to T substitution at nucleotide position 186, causing the glutamic acid (E) at amino acid position 62 to be replaced by an aspartic acid (D). 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	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.94	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.026	D;T;D
Sift4G	Benign	0.18	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.58
MutPred		0.22		Gain of ubiquitination at K59 (P = 0.0975);Gain of ubiquitination at K59 (P = 0.0975);Gain of ubiquitination at K59 (P = 0.0975);
MVP		0.48
MPC		0.21
ClinPred		0.92	D
GERP RS		3.8
Varity_R		0.32
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr4-101109230;