chr12-101920124-G-T

Variant names:

• chr12-101920124-G-T
• rs565616480
• NM_018370.3:c.595G>T

Variant summary

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

The NM_018370.3(DRAM1):​c.595G>T​(p.Val199Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 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: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: DRAM1 NM_018370.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.399

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRAM1	NM_018370.3	c.595G>T	p.Val199Leu	missense_variant	Exon 6 of 7	ENST00000258534.13	NP_060840.2
DRAM1	XM_047429098.1	c.421G>T	p.Val141Leu	missense_variant	Exon 6 of 7		XP_047285054.1
DRAM1	XM_005269005.3	c.358G>T	p.Val120Leu	missense_variant	Exon 4 of 5		XP_005269062.1
DRAM1	XM_005269004.3	c.580-1092G>T		intron_variant	Intron 5 of 5		XP_005269061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRAM1	ENST00000258534.13	c.595G>T	p.Val199Leu	missense_variant	Exon 6 of 7	1	NM_018370.3	ENSP00000258534.8

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.2
DANN	Benign	0.86
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.022
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.29
MutPred		0.46		Gain of helix (P = 0.132);
MVP		0.29
MPC		0.76
ClinPred		0.059	T
GERP RS		2.6
Varity_R		0.022
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: -15

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

Publications

LitVar

Other links and lift over

dbSNP: rs565616480; hg19: chr12-102313902;