rs697221

Variant names:

• chr12-57517377-G-A
• rs697221
• NM_004083.6:c.30C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-57517377-G-A
• chr12-57517377-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_004083.6(DDIT3):​c.30C>T​(p.Phe10Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,611,882 control chromosomes in the GnomAD database, including 19,096 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2524 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16572 hom.)
• Consequence: DDIT3 NM_004083.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• Publications: 37 publications found

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]

MARS1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2U

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• autosomal recessive spastic paraplegia type 70

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• spastic paraplegia 70, autosomal recessive

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• trichothiodystrophy 9, nonphotosensitive

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDIT3	NM_004083.6	c.30C>T	p.Phe10Phe	synonymous_variant	Exon 3 of 4	ENST00000346473.8	NP_004074.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDIT3	ENST00000346473.8	c.30C>T	p.Phe10Phe	synonymous_variant	Exon 3 of 4	1	NM_004083.6	ENSP00000340671.3

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26827 AN: 152004 Hom.: 2510 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.166 AC: 41329 AN: 248778 AF XY: 0.165

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.286

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.146 AC: 213695 AN: 1459758 Hom.: 16572 Cov.: 34 AF XY: 0.146 AC XY: 106281 AN XY: 726270

African (AFR) AF: 0.220 AC: 7354 AN: 33478

American (AMR) AF: 0.116 AC: 5187 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5198 AN: 26136

East Asian (EAS) AF: 0.217 AC: 8610 AN: 39698

South Asian (SAS) AF: 0.148 AC: 12802 AN: 86244

European-Finnish (FIN) AF: 0.228 AC: 11709 AN: 51418

Middle Eastern (MID) AF: 0.191 AC: 1103 AN: 5768

European-Non Finnish (NFE) AF: 0.137 AC: 152036 AN: 1111922

Other (OTH) AF: 0.161 AC: 9696 AN: 60378

GnomAD4 genome AF: 0.177 AC: 26872 AN: 152124 Hom.: 2524 Cov.: 32 AF XY: 0.182 AC XY: 13532 AN XY: 74360

African (AFR) AF: 0.221 AC: 9175 AN: 41484

American (AMR) AF: 0.142 AC: 2177 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 673 AN: 3472

East Asian (EAS) AF: 0.263 AC: 1359 AN: 5168

South Asian (SAS) AF: 0.160 AC: 772 AN: 4830

European-Finnish (FIN) AF: 0.226 AC: 2386 AN: 10576

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9692 AN: 67990

Other (OTH) AF: 0.172 AC: 363 AN: 2110

Alfa AF: 0.151 Hom.: 3019

Bravo AF: 0.175

Asia WGS AF: 0.175 AC: 612 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.1
DANN	Benign	0.67
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs697221; hg19: chr12-57911160; COSMIC: COSV56252135; COSMIC: COSV56252135;