1-111118183-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001349884.2(DRAM2):c.778C>T(p.Arg260Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000606 in 1,612,794 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R260Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (8 hom.)
• Consequence: DRAM2 NM_001349884.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.03

Genes affected

DRAM2 (HGNC:28769): (DNA damage regulated autophagy modulator 2) The protein encoded by this gene binds microtubule-associated protein 1 light chain 3 and is required for autophagy. Defects in this gene are a cause of retinal dystrophy. In addition, two microRNAs (microRNA 125b-1 and microRNA 144) can bind to the mRNA of this gene and produce the disease state. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004404843).
• BP6: Variant 1-111118183-G-A is Benign according to our data. Variant chr1-111118183-G-A is described in ClinVar as [Benign]. Clinvar id is 786853.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00311 (473/152050) while in subpopulation AFR AF= 0.011 (456/41538). AF 95% confidence interval is 0.0101. There are 3 homozygotes in gnomad4. There are 217 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DRAM2	NM_001349884.2	c.778C>T	p.Arg260Trp	missense_variant	10/10	ENST00000484310.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DRAM2	ENST00000484310.6	c.778C>T	p.Arg260Trp	missense_variant	10/10	1	NM_001349884.2	P1

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 473 AN: 151932 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

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: 0.0000295

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000888 AC: 223 AN: 251036 Hom.: 1 AF XY: 0.000663 AC XY: 90 AN XY: 135686

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000345 AC: 504 AN: 1460744 Hom.: 8 Cov.: 30 AF XY: 0.000296 AC XY: 215 AN XY: 726706

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.000582

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.00311 AC: 473 AN: 152050 Hom.: 3 Cov.: 32 AF XY: 0.00292 AC XY: 217 AN XY: 74344

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00127 Hom.: 1

Bravo AF: 0.00374

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00114 AC: 139

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.36	N
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.93	N;N
REVEL	Benign	0.12
Sift	Benign	0.19	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0	B;B
Vest4		0.071
MVP		0.31
MPC		0.14
ClinPred		0.036	T
GERP RS		2.9
Varity_R		0.038
gMVP		0.56

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

Other links and lift over

dbSNP: rs114734472; hg19: chr1-111660805; COSMIC: COSV99713302; COSMIC: COSV99713302;