Variant chr4-2904980-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001354761.2(ADD1):c.1378G>T(p.Gly460Trp) variant causes a missense change. The variant allele was found at a frequency of 0.198 in 1,613,978 control chromosomes in the GnomAD database, including 35,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.17 ( 2654 hom., cov: 32)

Exomes 𝑓: 0.20 ( 32571 hom. )

Consequence

ADD1
NM_001354761.2 missense

Scores

Clinical Significance

drug response reviewed by expert panel O:2

Conservation

PhyloP100: 5.68

Variant links:

Genes affected

ADD1 (HGNC:243): (adducin 1) Adducins are a family of cytoskeletal proteins encoded by three genes (alpha, beta, and gamma). Adducin acts as a heterodimer of the related alpha, beta, or gamma subunits. The protein encoded by this gene represents the alpha subunit. Alpha- and beta-adducin include a protease-resistant N-terminal region and a protease-sensitive, hydrophilic C-terminal region. Adducin binds with high affinity to Ca(2+)/calmodulin and is a substrate for protein kinases A and C. [provided by RefSeq, Aug 2017]

ADD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039125383).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADD1	NM_001354761.2 linkuse as main transcript	c.1378G>T	p.Gly460Trp	missense_variant	10/16	ENST00000683351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADD1	ENST00000683351.1 linkuse as main transcript	c.1378G>T	p.Gly460Trp	missense_variant	10/16		NM_001354761.2

Frequencies

GnomAD3 genomes

AF:

0.169

AC:

25648

AN:

152000

Hom.:

2654

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0794

Gnomad AMI

AF:

0.282

Gnomad AMR

AF:

0.182

Gnomad ASJ

AF:

0.147

Gnomad EAS

AF:

0.476

Gnomad SAS

AF:

0.189

Gnomad FIN

AF:

0.176

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.194

Gnomad OTH

AF:

0.150

GnomAD3 exomes

AF:

0.203

AC:

51062

AN:

251244

Hom.:

6182

AF XY:

0.201

AC XY:

27258

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.0779

Gnomad AMR exome

AF:

0.204

Gnomad ASJ exome

AF:

0.147

Gnomad EAS exome

AF:

0.468

Gnomad SAS exome

AF:

0.175

Gnomad FIN exome

AF:

0.185

Gnomad NFE exome

AF:

0.195

Gnomad OTH exome

AF:

0.193

GnomAD4 exome

AF:

0.201

AC:

294479

AN:

1461860

Hom.:

32571

Cov.:

AF XY:

0.200

AC XY:

145139

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0715

Gnomad4 AMR exome

AF:

0.198

Gnomad4 ASJ exome

AF:

0.149

Gnomad4 EAS exome

AF:

0.512

Gnomad4 SAS exome

AF:

0.174

Gnomad4 FIN exome

AF:

0.188

Gnomad4 NFE exome

AF:

0.199

Gnomad4 OTH exome

AF:

0.198

GnomAD4 genome

AF:

0.169

AC:

25663

AN:

152118

Hom.:

2654

Cov.:

AF XY:

0.168

AC XY:

12518

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0796

Gnomad4 AMR

AF:

0.183

Gnomad4 ASJ

AF:

0.147

Gnomad4 EAS

AF:

0.476

Gnomad4 SAS

AF:

0.187

Gnomad4 FIN

AF:

0.176

Gnomad4 NFE

AF:

0.194

Gnomad4 OTH

AF:

0.155

Alfa

AF:

0.191

Hom.:

6616

Bravo

AF:

0.168

TwinsUK

AF:

0.209

AC:

776

ALSPAC

AF:

0.198

AC:

763

ESP6500AA

AF:

0.0856

AC:

377

ESP6500EA

AF:

0.195

AC:

1678

ExAC

AF:

0.202

AC:

24520

Asia WGS

AF:

0.324

AC:

1125

AN:

3478

EpiCase

AF:

0.189

EpiControl

AF:

0.189

ClinVar

Significance: drug response

Submissions summary: Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

hydrochlorothiazide response - Efficacy

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy

Hypertension, salt-sensitive essential, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.089

.;.;T;T;.;.;D

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D;D;D;.;D

MetaRNN

Benign

0.0039

T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.1

M;M;.;.;M;M;M

MutationTaster

Benign

1.2e-8

P;P;P

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.3

N;N;N;N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.038

D;D;T;D;T;D;D

Sift4G

Uncertain

0.046

D;D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.;D

Vest4

0.43

MPC

0.92

ClinPred

0.0081

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.20

gMVP

0.28

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