12-101908252-A-C

Variant names:

• chr12-101908252-A-C
• rs1234792963
• NM_018370.3:c.409A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018370.3(DRAM1):​c.409A>C​(p.Thr137Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T137R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DRAM1 NM_018370.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.30
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018370.3. 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
	DRAM1	NM_018370.3	MANE Select	c.409A>C	p.Thr137Pro	missense	Exon 4 of 7	NP_060840.2	Q8N682-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRAM1	ENST00000258534.13	TSL:1 MANE Select	c.409A>C	p.Thr137Pro	missense	Exon 4 of 7	ENSP00000258534.8	Q8N682-1
	DRAM1	ENST00000549365.1	TSL:3	n.*396A>C		non_coding_transcript_exon	Exon 5 of 5	ENSP00000447171.1	H0YHJ0
	DRAM1	ENST00000549365.1	TSL:3	n.*396A>C		3_prime_UTR	Exon 5 of 5	ENSP00000447171.1	H0YHJ0

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249302 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.21
Sift	Benign	0.067	T
Sift4G	Benign	0.24	T
Polyphen		0.97	D
Vest4		0.65
MutPred		0.60		Loss of helix (P = 0.1299)
MVP		0.66
MPC		1.9
ClinPred		0.73	D
GERP RS		5.6
PromoterAI		-0.022	Neutral
Varity_R		0.42
gMVP		0.75
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs1234792963; hg19: chr12-102302030;