12-57516883-C-T

Position:

• chr12-57516883-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004083.6(DDIT3):​c.436G>A​(p.Glu146Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,613,918 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (11 hom.)
• Consequence: DDIT3 NM_004083.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.46

Genes affected

DDIT3 (HGNC:2726): (DNA damage inducible transcript 3) This gene encodes a member of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, such as C/EBP and LAP (liver activator protein), and preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis, is activated by endoplasmic reticulum stress, and promotes apoptosis. Fusion of this gene and FUS on chromosome 16 or EWSR1 on chromosome 22 induced by translocation generates chimeric proteins in myxoid liposarcomas or Ewing sarcoma. Multiple alternatively spliced transcript variants encoding two isoforms with different length have been identified. [provided by RefSeq, Aug 2010]

MARS1 (HGNC:6898): (methionyl-tRNA synthetase 1) This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. The encoded protein is a component of the multi-tRNA synthetase complex and catalyzes the ligation of methionine to tRNA molecules. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010696679).
• BP6: Variant 12-57516883-C-T is Benign according to our data. Variant chr12-57516883-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 703854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 304 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDIT3	NM_004083.6	c.436G>A	p.Glu146Lys	missense_variant	4/4	ENST00000346473.8	NP_004074.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDIT3	ENST00000346473.8	c.436G>A	p.Glu146Lys	missense_variant	4/4	1	NM_004083.6	ENSP00000340671	P1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00171 AC: 429 AN: 251300 Hom.: 2 AF XY: 0.00163 AC XY: 222 AN XY: 135846

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00186

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00249 AC: 3639 AN: 1461608 Hom.: 11 Cov.: 32 AF XY: 0.00233 AC XY: 1692 AN XY: 727140

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00216

Gnomad4 NFE exome AF: 0.00295

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.00175 AC XY: 130 AN XY: 74484

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00270 Hom.: 0

Bravo AF: 0.00228

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00151 AC: 183

EpiCase AF: 0.00267

EpiControl AF: 0.00356

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 14, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;D;.;D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	.;.;.;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.6	L;L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	D;.;D;D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Uncertain	0.021	D;.;D;D;D
Polyphen		0.97	D;D;.;D;.
Vest4		0.47
MVP		0.64
MPC		0.22
ClinPred		0.039	T
GERP RS		5.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.73
gMVP		0.20

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: rs112917609; hg19: chr12-57910666; COSMIC: COSV100007059; COSMIC: COSV100007059;