12-101908348-G-T

Variant names:

• chr12-101908348-G-T
• rs749800547
• NM_018370.3:c.505G>T

Variant summary

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

The NM_018370.3(DRAM1):​c.505G>T​(p.Ala169Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,626 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DRAM1 NM_018370.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.46

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=0.3109985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRAM1	NM_018370.3	c.505G>T	p.Ala169Ser	missense_variant	Exon 4 of 7	ENST00000258534.13	NP_060840.2
DRAM1	XM_005269004.3	c.505G>T	p.Ala169Ser	missense_variant	Exon 4 of 6		XP_005269061.1
DRAM1	XM_047429098.1	c.331G>T	p.Ala111Ser	missense_variant	Exon 4 of 7		XP_047285054.1
DRAM1	XM_005269005.3	c.342+6915G>T		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.505G>T	p.Ala169Ser	missense_variant	Exon 4 of 7	1	NM_018370.3	ENSP00000258534.8
DRAM1	ENST00000549365.1	n.*492G>T		downstream_gene_variant		3		ENSP00000447171.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457626 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724998

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.046
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.091
Sift	Benign	0.066	T
Sift4G	Benign	0.091	T
Polyphen		0.61	P
Vest4		0.39
MutPred		0.57		Gain of sheet (P = 0.039);
MVP		0.59
MPC		1.1
ClinPred		0.70	D
GERP RS		4.7
Varity_R		0.048
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs749800547; hg19: chr12-102302126;