chr1-111131424-C-T

Variant names:

• chr1-111131424-C-T
• rs786205665
• NM_001349884.2:c.131G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3 PP5_Moderate

The NM_001349886.2(DRAM2):​c.-28G>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000149 in 1,611,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: DRAM2 NM_001349886.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.32
• Publications: 4 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]

DRAM2 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 21

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 1-111131424-C-T is Pathogenic according to our data. Variant chr1-111131424-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 192238.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349886.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRAM2	NM_001349884.2	MANE Select	c.131G>A	p.Ser44Asn	missense splice_region	Exon 4 of 10	NP_001336813.1	Q6UX65
	DRAM2	NM_001349886.2		c.-28G>A		5_prime_UTR_premature_start_codon_gain	Exon 4 of 10	NP_001336815.1
	DRAM2	NM_001349887.2		c.-28G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	NP_001336816.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRAM2	ENST00000484310.6	TSL:1 MANE Select	c.131G>A	p.Ser44Asn	missense splice_region	Exon 4 of 10	ENSP00000503400.1	Q6UX65
	DRAM2	ENST00000286692.8	TSL:1	c.131G>A	p.Ser44Asn	missense splice_region	Exon 3 of 9	ENSP00000286692.4	Q6UX65
	DRAM2	ENST00000539140.6	TSL:1	c.131G>A	p.Ser44Asn	missense splice_region	Exon 3 of 9	ENSP00000437718.1	Q6UX65

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1459304 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 726026

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 85892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1110716

Other (OTH) AF: 0.0000166 AC: 1 AN: 60264

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74278

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000149 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cone-rod dystrophy 21 (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.88		Loss of glycosylation at S44 (P = 0.0061)
MVP		0.90
MPC		0.57
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.96
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
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

Other links and lift over

dbSNP: rs786205665; hg19: chr1-111674046;