Variant chr14-22589093-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001344.4(DAD1):c.65A>G(p.Gln22Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

DAD1
NM_001344.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.51

Variant links:

Genes affected

DAD1 (HGNC:2664): (defender against cell death 1) DAD1, the defender against apoptotic cell death, was initially identified as a negative regulator of programmed cell death in the temperature sensitive tsBN7 cell line. The DAD1 protein disappeared in temperature-sensitive cells following a shift to the nonpermissive temperature, suggesting that loss of the DAD1 protein triggered apoptosis. DAD1 is believed to be a tightly associated subunit of oligosaccharyltransferase both in the intact membrane and in the purified enzyme, thus reflecting the essential nature of N-linked glycosylation in eukaryotes. [provided by RefSeq, Jul 2008]

DAD1 links:

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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=0.0065298676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DAD1	NM_001344.4 linkuse as main transcript	c.65A>G	p.Gln22Arg	missense_variant	1/3	ENST00000250498.9	NP_001335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DAD1	ENST00000250498.9 linkuse as main transcript	c.65A>G	p.Gln22Arg	missense_variant	1/3	1	NM_001344.4	ENSP00000250498	P1
DAD1	ENST00000543337.1 linkuse as main transcript	c.65A>G	p.Gln22Arg	missense_variant	1/3	3		ENSP00000440821
DAD1	ENST00000538631.1 linkuse as main transcript	c.65A>G	p.Gln22Arg	missense_variant	1/2	2		ENSP00000440242
DAD1	ENST00000535847.1 linkuse as main transcript	c.65A>G	p.Gln22Arg	missense_variant, NMD_transcript_variant	1/3	2		ENSP00000442074

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000414

AC:

104

AN:

251408

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00873

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000243

AC:

355

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

182

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0102

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000309

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000523

Hom.:

Bravo

AF:

0.000355

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000354

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2021

The c.65A>G (p.Q22R) alteration is located in exon 1 (coding exon 1) of the DAD1 gene. This alteration results from a A to G substitution at nucleotide position 65, causing the glutamine (Q) at amino acid position 22 to be replaced by an arginine (R). 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

0.086

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T;T

Eigen

Benign

0.014

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.76

LIST_S2

Uncertain

0.89

D;D;T

M_CAP

Benign

0.0081

MetaRNN

Benign

0.0065

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;.

MutationTaster

Benign

0.96

D;D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.26

N;N;N

REVEL

Benign

0.071

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.023

B;.;.

Vest4

0.22

MVP

0.37

MPC

0.69

ClinPred

0.096

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.55

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