1-111118260-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001349884.2(DRAM2):c.701C>A(p.Ser234Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DRAM2 NM_001349884.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.00

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22743997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DRAM2	NM_001349884.2	c.701C>A	p.Ser234Tyr	missense_variant	10/10	ENST00000484310.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DRAM2	ENST00000484310.6	c.701C>A	p.Ser234Tyr	missense_variant	10/10	1	NM_001349884.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2023

This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 234 of the DRAM2 protein (p.Ser234Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DRAM2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DRAM2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	0.013
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.0080	B;B
Vest4		0.48
MutPred		0.45		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.34
MPC		0.19
ClinPred		0.96	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs917466805; hg19: chr1-111660882; COSMIC: COSV54415921; COSMIC: COSV54415921;