Genetic Variant DRAM1:p.Ser155Leu (chr12-101908307-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_018370.3(DRAM1):c.464C>T(p.Ser155Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

DRAM1
NM_018370.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.112

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=0.02411452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRAM1	NM_018370.3 link	c.464C>T	p.Ser155Leu	missense_variant	Exon 4 of 7	ENST00000258534.13	NP_060840.2	Q8N682-1A0A024RBF9
DRAM1	XM_005269004.3 link	c.464C>T	p.Ser155Leu	missense_variant	Exon 4 of 6		XP_005269061.1
DRAM1	XM_047429098.1 link	c.290C>T	p.Ser97Leu	missense_variant	Exon 4 of 7		XP_047285054.1
DRAM1	XM_005269005.3 link	c.342+6874C>T		intron_variant	Intron 3 of 4		XP_005269062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DRAM1	ENST00000258534.13 link	c.464C>T	p.Ser155Leu	missense_variant	Exon 4 of 7	1	NM_018370.3	ENSP00000258534.8	Q8N682-1
DRAM1	ENST00000549365.1 link	n.*451C>T		non_coding_transcript_exon_variant	Exon 5 of 5	3		ENSP00000447171.1	H0YHJ0
DRAM1	ENST00000549365.1 link	n.*451C>T		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000447171.1	H0YHJ0

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000922

AC:

AN:

249382

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135296

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000619

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000711

AC:

104

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000909

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.464C>T (p.S155L) alteration is located in exon 4 (coding exon 4) of the DRAM1 gene. This alteration results from a C to T substitution at nucleotide position 464, causing the serine (S) at amino acid position 155 to be replaced by a leucine (L). 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

0.071

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.64

CADD

Benign

3.3

DANN

Benign

0.68

DEOGEN2

Benign

0.20

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.70

M_CAP

Benign

0.0029

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.66

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.0

REVEL

Benign

0.016

Sift

Benign

0.58

Sift4G

Benign

0.71

Polyphen

0.0010

Vest4

0.30

MVP

0.12

MPC

0.67

ClinPred

0.0057

GERP RS

-5.4

Varity_R

0.015

gMVP

0.15

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