rs11194996

Positions:

• chr10-110129967-C-G
• chr10-110129967-C-T

Variant summary

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

The NM_016824.5(ADD3):​c.1609-396C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 152,076 control chromosomes in the GnomAD database, including 4,269 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 0.13 (4269 hom., cov: 32)
• Consequence: ADD3 NM_016824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.274

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADD3	NM_016824.5	c.1609-396C>G		intron_variant		ENST00000356080.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADD3	ENST00000356080.9	c.1609-396C>G		intron_variant		1	NM_016824.5	A1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20002 AN: 151958 Hom.: 4244 Cov.: 32

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0574

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00373

Gnomad OTH AF: 0.102

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

GnomAD4 genome AF: 0.132 AC: 20074 AN: 152076 Hom.: 4269 Cov.: 32 AF XY: 0.128 AC XY: 9499 AN XY: 74350

Gnomad4 AFR AF: 0.448

Gnomad4 AMR AF: 0.0572

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00373

Gnomad4 OTH AF: 0.101

Alfa AF: 0.0268 Hom.: 79

Bravo AF: 0.151

Asia WGS AF: 0.0420 AC: 144 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.3
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11194996; hg19: chr10-111889725;