chr12-101908252-A-G

Position:

• chr12-101908252-A-G

Variant summary

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

The NM_018370.3(DRAM1):​c.409A>G​(p.Thr137Ala) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DRAM1 NM_018370.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26017845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRAM1	NM_018370.3	c.409A>G	p.Thr137Ala	missense_variant	4/7	ENST00000258534.13	NP_060840.2
DRAM1	XM_005269004.3	c.409A>G	p.Thr137Ala	missense_variant	4/6		XP_005269061.1
DRAM1	XM_047429098.1	c.235A>G	p.Thr79Ala	missense_variant	4/7		XP_047285054.1
DRAM1	XM_005269005.3	c.342+6819A>G		intron_variant			XP_005269062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRAM1	ENST00000258534.13	c.409A>G	p.Thr137Ala	missense_variant	4/7	1	NM_018370.3	ENSP00000258534.8
DRAM1	ENST00000549365.1	n.*396A>G		non_coding_transcript_exon_variant	5/5	3		ENSP00000447171.1
DRAM1	ENST00000549365.1	n.*396A>G		3_prime_UTR_variant	5/5	3		ENSP00000447171.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.409A>G (p.T137A) 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 409, causing the threonine (T) at amino acid position 137 to be replaced by an alanine (A). 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	0.16
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.081
Sift	Benign	0.42	T
Sift4G	Benign	0.76	T
Polyphen		0.0090	B
Vest4		0.54
MutPred		0.32		Gain of helix (P = 0.132);
MVP		0.45
MPC		0.78
ClinPred		0.59	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.071
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-102302030;