NM_019058.4:c.397C>T

Variant names:

• chr10-72274886-C-T
• NM_019058.4:c.397C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_019058.4(DDIT4):​c.397C>T​(p.Arg133Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DDIT4 NM_019058.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38
• Publications: 0 publications found

Genes affected

DDIT4 (HGNC:24944): (DNA damage inducible transcript 4) Predicted to enable 14-3-3 protein binding activity. Involved in defense response to virus; negative regulation of TOR signaling; and response to hypoxia. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

DDIT4-AS1 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a mutagenesis_site No effect on inhibition of mTORC1. (size 0) in uniprot entity DDIT4_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019058.4. 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
	DDIT4	NM_019058.4	MANE Select	c.397C>T	p.Arg133Cys	missense	Exon 3 of 3	NP_061931.1	Q9NX09

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDIT4	ENST00000307365.4	TSL:1 MANE Select	c.397C>T	p.Arg133Cys	missense	Exon 3 of 3	ENSP00000307305.3	Q9NX09
	DDIT4	ENST00000473155.2	TSL:1	n.690C>T		non_coding_transcript_exon	Exon 2 of 2
	DDIT4	ENST00000871236.1		c.397C>T	p.Arg133Cys	missense	Exon 3 of 3	ENSP00000541295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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	Uncertain	0.40
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.79		Gain of catalytic residue at L134 (P = 0.0098)
MVP		0.75
MPC		1.4
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.57
Mutation Taster		=39/61	disease causing

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

hg19: chr10-74034644;