10-110126331-G-A

Position:

• chr10-110126331-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016824.5(ADD3):​c.1522-86G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 1,003,096 control chromosomes in the GnomAD database, including 219,547 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 0.71 (40424 hom., cov: 31)
  • Exomes 𝑓: 0.63 (179123 hom.)
• Consequence: ADD3 NM_016824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0260

Genes affected

ADD3 (HGNC:245): (adducin 3) Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta and gamma. The three subunits are encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. While adducins alpha and gamma are ubiquitously expressed, the expression of adducin beta is restricted to brain and hematopoietic tissues. Adducin, originally purified from human erythrocytes, was found to be a heterodimer of adducins alpha and beta. Polymorphisms resulting in amino acid substitutions in these two subunits have been associated with the regulation of blood pressure in an animal model of hypertension. Heterodimers consisting of alpha and gamma subunits have also been described. Structurally, each subunit is comprised of two distinct domains. The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Alternatively spliced adducin gamma transcripts encoding different isoforms have been described. The functions of the different isoforms are not known. [provided by RefSeq, Jul 2008]

ADD3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADD3	NM_016824.5	c.1522-86G>A		intron_variant		ENST00000356080.9	NP_058432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADD3	ENST00000356080.9	c.1522-86G>A		intron_variant		1	NM_016824.5	ENSP00000348381.4

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107542 AN: 151970 Hom.: 40346 Cov.: 31

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.658

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.870

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.705

GnomAD4 exome AF: 0.635 AC: 540312 AN: 851008 Hom.: 179123 AF XY: 0.642 AC XY: 284368 AN XY: 442876

Gnomad4 AFR exome AF: 0.936

Gnomad4 AMR exome AF: 0.769

Gnomad4 ASJ exome AF: 0.656

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.860

Gnomad4 FIN exome AF: 0.516

Gnomad4 NFE exome AF: 0.572

Gnomad4 OTH exome AF: 0.668

GnomAD4 genome AF: 0.708 AC: 107683 AN: 152088 Hom.: 40424 Cov.: 31 AF XY: 0.710 AC XY: 52751 AN XY: 74336

Gnomad4 AFR AF: 0.925

Gnomad4 AMR AF: 0.754

Gnomad4 ASJ AF: 0.658

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.871

Gnomad4 FIN AF: 0.504

Gnomad4 NFE AF: 0.567

Gnomad4 OTH AF: 0.709

Alfa AF: 0.607 Hom.: 26725

Bravo AF: 0.734

Asia WGS AF: 0.926 AC: 3218 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.8
DANN	Benign	0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs3731566; hg19: chr10-111886089;