Genetic Variant NM_001349884.2:c.-79+5G>A (chr1-111139496-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Variant links:

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]

DRAM2 links:

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]

CEPT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRAM2	NM_001349884.2 link	c.-79+5G>A		splice_region_variant, intron_variant	Intron 2 of 9	ENST00000484310.6	NP_001336813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRAM2	ENST00000484310.6 link	c.-79+5G>A		splice_region_variant, intron_variant	Intron 2 of 9	1	NM_001349884.2	ENSP00000503400.1		Q6UX65

Frequencies

GnomAD3 genomes

AF:

0.257

AC:

39126

AN:

151980

Hom.:

5110

Cov.:

show subpopulations

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:

AN:

Hom.:

Cov.:

AF XY:

0.125

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.222

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.154

AC:

AN:

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.257

AC:

39138

AN:

152098

Hom.:

5109

Cov.:

AF XY:

0.257

AC XY:

19140

AN XY:

74356

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.281

AC:

19129

AN:

67974

Other (OTH)

AF:

0.238

AC:

503

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1536

3072

4607

6143

7679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

418

836

1254

1672

2090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.14

PromoterAI

-0.035

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over