4-2856278-A-G

Variant names:

• chr4-2856278-A-G
• rs1263412
• NM_001354761.2:c.-21+12254A>G

Variant summary

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

The NM_001354761.2(ADD1):​c.-21+12254A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 151,908 control chromosomes in the GnomAD database, including 7,815 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7815 hom., cov: 31)
• Consequence: ADD1 NM_001354761.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.397
• Publications: 5 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 (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354761.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD1	NM_001354761.2	MANE Select	c.-21+12254A>G		intron	N/A	NP_001341690.1
	ADD1	NM_001354756.2		c.-21+12254A>G		intron	N/A	NP_001341685.1
	ADD1	NM_014189.4		c.-21+12254A>G		intron	N/A	NP_054908.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD1	ENST00000683351.1	MANE Select	c.-21+12254A>G		intron	N/A	ENSP00000508142.1
	ADD1	ENST00000355842.7	TSL:1	c.-179+11444A>G		intron	N/A	ENSP00000348100.3
	ADD1	ENST00000264758.11	TSL:5	c.-21+12254A>G		intron	N/A	ENSP00000264758.6

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47266 AN: 151790 Hom.: 7806 Cov.: 31

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.0360

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.298

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.311 AC: 47312 AN: 151908 Hom.: 7815 Cov.: 31 AF XY: 0.307 AC XY: 22803 AN XY: 74248

African (AFR) AF: 0.384 AC: 15895 AN: 41398

American (AMR) AF: 0.233 AC: 3551 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1002 AN: 3466

East Asian (EAS) AF: 0.0361 AC: 187 AN: 5180

South Asian (SAS) AF: 0.137 AC: 662 AN: 4818

European-Finnish (FIN) AF: 0.381 AC: 4002 AN: 10500

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.309 AC: 21007 AN: 67970

Other (OTH) AF: 0.295 AC: 622 AN: 2108

Alfa AF: 0.251 Hom.: 1129

Bravo AF: 0.305

Asia WGS AF: 0.111 AC: 384 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.0
DANN	Benign	0.84
PhyloP100		-0.40
Mutation Taster		=100/0	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: rs1263412; hg19: chr4-2858005;