Variant 12-101877907-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018370.3(DRAM1):c.118C>T(p.Leu40Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000462 in 1,537,968 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

DRAM1
NM_018370.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.646

Variant links:

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]

DRAM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03699106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DRAM1	NM_018370.3 linkuse as main transcript	c.118C>T	p.Leu40Phe	missense_variant	1/7	ENST00000258534.13
DRAM1	XM_005269004.3 linkuse as main transcript	c.118C>T	p.Leu40Phe	missense_variant	1/6
DRAM1	XM_005269005.3 linkuse as main transcript	c.118C>T	p.Leu40Phe	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DRAM1	ENST00000258534.13 linkuse as main transcript	c.118C>T	p.Leu40Phe	missense_variant	1/7	1	NM_018370.3	P1	Q8N682-1
DRAM1	ENST00000544152.5 linkuse as main transcript	c.118C>T	p.Leu40Phe	missense_variant	1/4	2			Q8N682-2
DRAM1	ENST00000551403.1 linkuse as main transcript	c.118C>T	p.Leu40Phe	missense_variant, NMD_transcript_variant	1/6	5
DRAM1	ENST00000549365.1 linkuse as main transcript	c.112C>T	p.Leu38Phe	missense_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000106

AC:

AN:

150698

Hom.:

AF XY:

0.0000620

AC XY:

AN XY:

80700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00164

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000336

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000483

AC:

AN:

1385760

Hom.:

Cov.:

AF XY:

0.0000336

AC XY:

AN XY:

684276

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00181

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000177

Gnomad4 OTH exome

AF:

0.0000524

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000140

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000445

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.118C>T (p.L40F) alteration is located in exon 1 (coding exon 1) of the DRAM1 gene. This alteration results from a C to T substitution at nucleotide position 118, causing the leucine (L) at amino acid position 40 to be replaced by a phenylalanine (F). 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

-0.28

BayesDel_noAF

Benign

-0.53

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.78

T;D

M_CAP

Benign

0.0085

MetaRNN

Benign

0.037

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.28

N;N

MutationTaster

Benign

0.92

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.27

N;N

REVEL

Benign

0.065

Sift

Benign

0.38

T;T

Sift4G

Benign

0.64

T;T

Polyphen

0.0050

B;.

Vest4

0.17

MVP

0.17

MPC

0.85

ClinPred

0.029

GERP RS

2.8

Varity_R

0.050

gMVP

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over