20-62881463-T-G

Position:

• chr20-62881463-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001193369.2(DIDO1):​c.4493A>C​(p.Glu1498Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,609,888 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: DIDO1 NM_001193369.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.42

Genes affected

DIDO1 (HGNC:2680): (death inducer-obliterator 1) Apoptosis, a major form of cell death, is an efficient mechanism for eliminating unwanted cells and is of central importance for development and homeostasis in metazoan animals. In mice, the death inducer-obliterator-1 gene is upregulated by apoptotic signals and encodes a cytoplasmic protein that translocates to the nucleus upon apoptotic signal activation. When overexpressed, the mouse protein induced apoptosis in cell lines growing in vitro. This gene is similar to the mouse gene and therefore is thought to be involved in apoptosis. Alternatively spliced transcripts have been found for this gene, encoding multiple isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005387664).
• BP6: Variant 20-62881463-T-G is Benign according to our data. Variant chr20-62881463-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 726109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 240 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIDO1	NM_001193369.2	c.4493A>C	p.Glu1498Ala	missense_variant	16/16	ENST00000395343.6	NP_001180298.1
DIDO1	NM_033081.3	c.4493A>C	p.Glu1498Ala	missense_variant	16/16		NP_149072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIDO1	ENST00000395343.6	c.4493A>C	p.Glu1498Ala	missense_variant	16/16	1	NM_001193369.2	ENSP00000378752	P2
DIDO1	ENST00000266070.8	c.4493A>C	p.Glu1498Ala	missense_variant	16/16	5		ENSP00000266070	P2

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 239 AN: 151922 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00537

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

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: 0.0000735

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000434 AC: 108 AN: 249072 Hom.: 0 AF XY: 0.000296 AC XY: 40 AN XY: 135052

Gnomad AFR exome AF: 0.00531

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000499

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000215 AC: 314 AN: 1457848 Hom.: 1 Cov.: 36 AF XY: 0.000194 AC XY: 141 AN XY: 725378

Gnomad4 AFR exome AF: 0.00496

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152040 Hom.: 1 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74302

Gnomad4 AFR AF: 0.00538

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000847 Hom.: 2

Bravo AF: 0.00184

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000667 AC: 81

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 09, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	T;.
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.60	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.052
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.28	T;T
Polyphen		0.022	B;B
Vest4		0.17
MVP		0.17
MPC		0.40
ClinPred		0.033	T
GERP RS		2.2
Varity_R		0.13
gMVP		0.25

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs112393443; hg19: chr20-61512815;