chr4-2904980-G-T

Variant names:

• chr4-2904980-G-T
• rs4961
• NM_001354761.2:c.1378G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: drug response reviewed by expert panel O:2
• Conservation: PhyloP100: 5.68
• Publications: 360 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ADD1	NM_001354761.2	c.1378G>T	p.Gly460Trp	missense_variant	Exon 10 of 16	ENST00000683351.1	NP_001341690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADD1	ENST00000683351.1	c.1378G>T	p.Gly460Trp	missense_variant	Exon 10 of 16		NM_001354761.2	ENSP00000508142.1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25648 AN: 152000 Hom.: 2654 Cov.: 32

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

GnomAD2 exomes AF: 0.203 AC: 51062 AN: 251244 AF XY: 0.201

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 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.: 33 AF XY: 0.200 AC XY: 145139 AN XY: 727232

African (AFR) AF: 0.0715 AC: 2395 AN: 33480

American (AMR) AF: 0.198 AC: 8841 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 3890 AN: 26136

East Asian (EAS) AF: 0.512 AC: 20332 AN: 39700

South Asian (SAS) AF: 0.174 AC: 15036 AN: 86256

European-Finnish (FIN) AF: 0.188 AC: 10056 AN: 53416

Middle Eastern (MID) AF: 0.0924 AC: 533 AN: 5768

European-Non Finnish (NFE) AF: 0.199 AC: 221459 AN: 1111992

Other (OTH) AF: 0.198 AC: 11937 AN: 60396

GnomAD4 genome AF: 0.169 AC: 25663 AN: 152118 Hom.: 2654 Cov.: 32 AF XY: 0.168 AC XY: 12518 AN XY: 74344

African (AFR) AF: 0.0796 AC: 3303 AN: 41514

American (AMR) AF: 0.183 AC: 2788 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 511 AN: 3470

East Asian (EAS) AF: 0.476 AC: 2456 AN: 5158

South Asian (SAS) AF: 0.187 AC: 901 AN: 4824

European-Finnish (FIN) AF: 0.176 AC: 1867 AN: 10582

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.194 AC: 13216 AN: 67986

Other (OTH) AF: 0.155 AC: 326 AN: 2110

Alfa AF: 0.189 Hom.: 12964

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

Submissions by phenotype

hydrochlorothiazide response - Efficacy Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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

Feb 01, 1999

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;T;T;.;.;D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
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	T
MutationAssessor	Uncertain	2.1	M;M;.;.;M;M;M
PhyloP100		5.7
PrimateAI	Uncertain	0.77	T
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
Vest4		0.43
ClinPred		0.0081	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.20
gMVP		0.28
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4961; hg19: chr4-2906707; COSMIC: COSV53268966; COSMIC: COSV53268966;