20-62881941-T-A

Position:

• chr20-62881941-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001193369.2(DIDO1):​c.4015A>T​(p.Thr1339Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,613,360 control chromosomes in the GnomAD database, including 43 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (21 hom.)
• Consequence: DIDO1 NM_001193369.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.310

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026710927).
• BP6: Variant 20-62881941-T-A is Benign according to our data. Variant chr20-62881941-T-A is described in ClinVar as [Benign]. Clinvar id is 777609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00913 (1391/152300) while in subpopulation AFR AF= 0.0319 (1324/41560). AF 95% confidence interval is 0.0304. There are 22 homozygotes in gnomad4. There are 621 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1391 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIDO1	NM_001193369.2	c.4015A>T	p.Thr1339Ser	missense_variant	16/16	ENST00000395343.6	NP_001180298.1
DIDO1	NM_033081.3	c.4015A>T	p.Thr1339Ser	missense_variant	16/16		NP_149072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIDO1	ENST00000395343.6	c.4015A>T	p.Thr1339Ser	missense_variant	16/16	1	NM_001193369.2	ENSP00000378752	P2
DIDO1	ENST00000266070.8	c.4015A>T	p.Thr1339Ser	missense_variant	16/16	5		ENSP00000266070	P2

Frequencies

GnomAD3 genomes AF: 0.00907 AC: 1381 AN: 152182 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

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: 0.000162

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00238 AC: 596 AN: 250670 Hom.: 7 AF XY: 0.00177 AC XY: 240 AN XY: 135796

Gnomad AFR exome AF: 0.0321

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000984 AC: 1437 AN: 1461060 Hom.: 21 Cov.: 36 AF XY: 0.000837 AC XY: 608 AN XY: 726798

Gnomad4 AFR exome AF: 0.0323

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00913 AC: 1391 AN: 152300 Hom.: 22 Cov.: 32 AF XY: 0.00834 AC XY: 621 AN XY: 74482

Gnomad4 AFR AF: 0.0319

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00229 Hom.: 1

Bravo AF: 0.0103

ESP6500AA AF: 0.0281 AC: 124

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00300 AC: 364

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.062
DANN	Benign	0.34
DEOGEN2	Benign	0.067	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.21	T;.
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.36	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.70	N;N
REVEL	Benign	0.054
Sift	Benign	0.43	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.0050	B;B
Vest4		0.044
MutPred		0.17		Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP		0.31
MPC		0.33
ClinPred		0.0011	T
GERP RS		-9.8
Varity_R		0.023
gMVP		0.059

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs75790071; hg19: chr20-61513293;