1-111120671-T-C

Variant names:

• chr1-111120671-T-C
• rs786205664
• NM_001349884.2:c.362A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001349884.2(DRAM2):​c.362A>G​(p.His121Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000708 in 1,413,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H121L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DRAM2 NM_001349884.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.83
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a chain DNA damage-regulated autophagy modulator protein 2 (size 265) in uniprot entity DRAM2_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_001349884.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-111120671-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 192237.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRAM2	NM_001349884.2	MANE Select	c.362A>G	p.His121Arg	missense	Exon 7 of 10	NP_001336813.1	Q6UX65
	DRAM2	NM_001349881.2		c.362A>G	p.His121Arg	missense	Exon 7 of 10	NP_001336810.1	Q6UX65
	DRAM2	NM_001349882.2		c.362A>G	p.His121Arg	missense	Exon 7 of 10	NP_001336811.1	Q6UX65

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRAM2	ENST00000484310.6	TSL:1 MANE Select	c.362A>G	p.His121Arg	missense	Exon 7 of 10	ENSP00000503400.1	Q6UX65
	DRAM2	ENST00000286692.8	TSL:1	c.362A>G	p.His121Arg	missense	Exon 6 of 9	ENSP00000286692.4	Q6UX65
	DRAM2	ENST00000539140.6	TSL:1	c.362A>G	p.His121Arg	missense	Exon 6 of 9	ENSP00000437718.1	Q6UX65

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1413304 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 701956

African (AFR) AF: 0.00 AC: 0 AN: 30834

American (AMR) AF: 0.00 AC: 0 AN: 37550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24398

East Asian (EAS) AF: 0.00 AC: 0 AN: 37582

South Asian (SAS) AF: 0.00 AC: 0 AN: 78854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088234

Other (OTH) AF: 0.00 AC: 0 AN: 58084

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.93		Gain of solvent accessibility (P = 0.0584)
MVP		0.92
MPC		0.67
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.96
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs786205664; hg19: chr1-111663293;