rs4963

Variant names:

• chr4-2915035-C-G
• rs4963
• NM_001354761.2:c.1943C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-2915035-C-G
• chr4-2915035-C-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.1943C>G​(p.Ser648Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,610,858 control chromosomes in the GnomAD database, including 32,157 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (2889 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29268 hom.)
• Consequence: ADD1 NM_001354761.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75
• Publications: 58 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=7.816255E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADD1	NM_001354761.2	c.1943C>G	p.Ser648Cys	missense_variant	Exon 14 of 16	ENST00000683351.1	NP_001341690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADD1	ENST00000683351.1	c.1943C>G	p.Ser648Cys	missense_variant	Exon 14 of 16		NM_001354761.2	ENSP00000508142.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28344 AN: 152060 Hom.: 2884 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.161

GnomAD2 exomes AF: 0.204 AC: 49926 AN: 245190 AF XY: 0.199

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.468

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.191 AC: 279106 AN: 1458680 Hom.: 29268 Cov.: 32 AF XY: 0.189 AC XY: 137409 AN XY: 725510

African (AFR) AF: 0.168 AC: 5624 AN: 33396

American (AMR) AF: 0.200 AC: 8844 AN: 44226

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4308 AN: 25908

East Asian (EAS) AF: 0.513 AC: 20296 AN: 39594

South Asian (SAS) AF: 0.173 AC: 14816 AN: 85848

European-Finnish (FIN) AF: 0.183 AC: 9745 AN: 53338

Middle Eastern (MID) AF: 0.0971 AC: 559 AN: 5756

European-Non Finnish (NFE) AF: 0.183 AC: 203257 AN: 1110392

Other (OTH) AF: 0.194 AC: 11657 AN: 60222

GnomAD4 genome AF: 0.186 AC: 28379 AN: 152178 Hom.: 2889 Cov.: 32 AF XY: 0.187 AC XY: 13899 AN XY: 74382

African (AFR) AF: 0.167 AC: 6920 AN: 41530

American (AMR) AF: 0.188 AC: 2880 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 577 AN: 3470

East Asian (EAS) AF: 0.478 AC: 2466 AN: 5164

South Asian (SAS) AF: 0.187 AC: 903 AN: 4830

European-Finnish (FIN) AF: 0.174 AC: 1841 AN: 10592

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12214 AN: 67986

Other (OTH) AF: 0.166 AC: 350 AN: 2110

Alfa AF: 0.176 Hom.: 755

Bravo AF: 0.190

TwinsUK AF: 0.191 AC: 707

ALSPAC AF: 0.186 AC: 716

ESP6500AA AF: 0.176 AC: 777

ESP6500EA AF: 0.184 AC: 1582

ExAC AF: 0.202 AC: 24543

Asia WGS AF: 0.332 AC: 1155 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.0	.;.;T;T;.;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.37	T;T;T;T;T;.;T
MetaRNN	Benign	0.00078	T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	.;.;.;.;.;.;L
PhyloP100		1.8
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.94	N;N;N;N;N;N;N
REVEL	Benign	0.089
Sift	Benign	0.054	T;T;T;T;T;T;T
Sift4G	Uncertain	0.053	T;T;T;T;T;T;T
Vest4		0.096
ClinPred		0.026	T
GERP RS		4.6
PromoterAI		0.0094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.074
gMVP		0.092
Mutation Taster		=93/7	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: rs4963; hg19: chr4-2916762; COSMIC: COSV53268983;