20-62880593-G-A

Position:

• chr20-62880593-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001193369.2(DIDO1):​c.5363C>T​(p.Ser1788Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DIDO1 NM_001193369.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13806245).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIDO1	NM_001193369.2	c.5363C>T	p.Ser1788Phe	missense_variant	16/16	ENST00000395343.6	NP_001180298.1
DIDO1	NM_033081.3	c.5363C>T	p.Ser1788Phe	missense_variant	16/16		NP_149072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIDO1	ENST00000395343.6	c.5363C>T	p.Ser1788Phe	missense_variant	16/16	1	NM_001193369.2	ENSP00000378752	P2
DIDO1	ENST00000266070.8	c.5363C>T	p.Ser1788Phe	missense_variant	16/16	5		ENSP00000266070	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460572 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726566

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

The c.5363C>T (p.S1788F) alteration is located in exon 16 (coding exon 14) of the DIDO1 gene. This alteration results from a C to T substitution at nucleotide position 5363, causing the serine (S) at amino acid position 1788 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	0.19
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.55	T;.
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.058
Sift	Uncertain	0.028	D;D
Sift4G	Uncertain	0.054	T;T
Polyphen		0.72	P;P
Vest4		0.13
MutPred		0.14		Loss of glycosylation at S1788 (P = 0.0046);Loss of glycosylation at S1788 (P = 0.0046);
MVP		0.19
MPC		0.90
ClinPred		0.36	T
GERP RS		3.5
Varity_R		0.056
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: rs2064183099; hg19: chr20-61511945;