rs3762374

Positions:

• chr1-111139496-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001349884.2(DRAM2):​c.-79+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 152,178 control chromosomes in the GnomAD database, including 5,110 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (5109 hom., cov: 32)
  • Exomes 𝑓: 0.17 (1 hom.)
• Consequence: DRAM2 NM_001349884.2 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.00007455
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.140

Genes affected

DRAM2 (HGNC:28769): (DNA damage regulated autophagy modulator 2) The protein encoded by this gene binds microtubule-associated protein 1 light chain 3 and is required for autophagy. Defects in this gene are a cause of retinal dystrophy. In addition, two microRNAs (microRNA 125b-1 and microRNA 144) can bind to the mRNA of this gene and produce the disease state. [provided by RefSeq, Mar 2017]

CEPT1 (HGNC:24289): (choline/ethanolamine phosphotransferase 1) This gene codes for a choline/ethanolaminephosphotransferase, which functions in the synthesis of choline- or ethanolamine- containing phospholipids. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRAM2	NM_001349884.2	c.-79+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000484310.6	NP_001336813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRAM2	ENST00000484310.6	c.-79+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_001349884.2	ENSP00000503400	P1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39126 AN: 151980 Hom.: 5110 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.239

GnomAD4 exome AF: 0.175 AC: 14 AN: 80 Hom.: 1 Cov.: 0 AF XY: 0.125 AC XY: 7 AN XY: 56

Gnomad4 FIN exome AF: 0.222

Gnomad4 NFE exome AF: 0.154

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.257 AC: 39138 AN: 152098 Hom.: 5109 Cov.: 32 AF XY: 0.257 AC XY: 19140 AN XY: 74356

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.226

Gnomad4 EAS AF: 0.379

Gnomad4 SAS AF: 0.230

Gnomad4 FIN AF: 0.328

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.238

Alfa AF: 0.267 Hom.: 8207

Bravo AF: 0.248

Asia WGS AF: 0.278 AC: 964 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000075
dbscSNV1_RF	Benign	0.036
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.61		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs3762374; hg19: chr1-111682118;