12-101908320-A-G

Variant names:

• chr12-101908320-A-G
• rs1433890655
• NM_018370.3:c.477A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018370.3(DRAM1):​c.477A>G​(p.Ile159Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DRAM1 NM_018370.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.49

Genes affected

DRAM1 (HGNC:25645): (DNA damage regulated autophagy modulator 1) This gene is regulated as part of the p53 tumor suppressor pathway. The gene encodes a lysosomal membrane protein that is required for the induction of autophagy by the pathway. Decreased transcriptional expression of this gene is associated with various tumors. This gene has a pseudogene on chromosome 4. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40608793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRAM1	NM_018370.3	c.477A>G	p.Ile159Met	missense_variant	Exon 4 of 7	ENST00000258534.13	NP_060840.2
DRAM1	XM_005269004.3	c.477A>G	p.Ile159Met	missense_variant	Exon 4 of 6		XP_005269061.1
DRAM1	XM_047429098.1	c.303A>G	p.Ile101Met	missense_variant	Exon 4 of 7		XP_047285054.1
DRAM1	XM_005269005.3	c.342+6887A>G		intron_variant	Intron 3 of 4		XP_005269062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRAM1	ENST00000258534.13	c.477A>G	p.Ile159Met	missense_variant	Exon 4 of 7	1	NM_018370.3	ENSP00000258534.8
DRAM1	ENST00000549365.1	n.*464A>G		non_coding_transcript_exon_variant	Exon 5 of 5	3		ENSP00000447171.1
DRAM1	ENST00000549365.1	n.*464A>G		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000447171.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.477A>G (p.I159M) alteration is located in exon 4 (coding exon 4) of the DRAM1 gene. This alteration results from a A to G substitution at nucleotide position 477, causing the isoleucine (I) at amino acid position 159 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.7
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.027	D
Polyphen		0.37	B
Vest4		0.45
MutPred		0.60		Gain of methylation at R160 (P = 0.1187);
MVP		0.31
MPC		1.4
ClinPred		0.18	T
GERP RS		-11
Varity_R		0.080
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1433890655; hg19: chr12-102302098;