rs3762374

Variant names:

• chr1-111139496-C-T
• rs3762374
• NM_001349884.2:c.-79+5G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001349884.2(DRAM2):​c.-79+5G>A variant causes a splice region, 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_region, intron
• Scores: Splicing: ADA: 0.00007455
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.140
• Publications: 38 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349884.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRAM2	NM_001349884.2	MANE Select	c.-79+5G>A		splice_region intron	N/A	NP_001336813.1
	DRAM2	NM_001349881.2		c.-79+5G>A		splice_region intron	N/A	NP_001336810.1
	DRAM2	NM_001349882.2		c.-79+92G>A		intron	N/A	NP_001336811.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRAM2	ENST00000484310.6	TSL:1 MANE Select	c.-79+5G>A		splice_region intron	N/A	ENSP00000503400.1
	DRAM2	ENST00000286692.8	TSL:1	c.-79+5G>A		splice_region intron	N/A	ENSP00000286692.4
	DRAM2	ENST00000539140.6	TSL:1	c.-79+542G>A		intron	N/A	ENSP00000437718.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.222 AC: 4 AN: 18

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.154 AC: 8 AN: 52

Other (OTH) AF: 0.250 AC: 2 AN: 8

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

African (AFR) AF: 0.212 AC: 8785 AN: 41496

American (AMR) AF: 0.209 AC: 3202 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 783 AN: 3472

East Asian (EAS) AF: 0.379 AC: 1957 AN: 5166

South Asian (SAS) AF: 0.230 AC: 1108 AN: 4822

European-Finnish (FIN) AF: 0.328 AC: 3462 AN: 10562

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19129 AN: 67974

Other (OTH) AF: 0.238 AC: 503 AN: 2114

Alfa AF: 0.267 Hom.: 12166

Bravo AF: 0.248

Asia WGS AF: 0.278 AC: 964 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		0.14
PromoterAI		-0.035	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3762374; hg19: chr1-111682118;