rs2501575

Variant names:

• chr10-110090106-G-A
• rs2501575
• NM_016824.5:c.-29-10519G>A

Variant summary

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

The NM_016824.5(ADD3):​c.-29-10519G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 151,682 control chromosomes in the GnomAD database, including 14,265 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 0.35 (14265 hom., cov: 31)
• Consequence: ADD3 NM_016824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.175
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• cerebral palsy, spastic quadriplegic, 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• complex neurodevelopmental disorder with motor features

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• spastic quadriplegic cerebral palsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016824.5. 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
	ADD3	NM_016824.5	MANE Select	c.-29-10519G>A		intron	N/A	NP_058432.1
	ADD3	NM_001320591.2		c.-29-10519G>A		intron	N/A	NP_001307520.1
	ADD3	NM_001320592.2		c.-29-10519G>A		intron	N/A	NP_001307521.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADD3	ENST00000356080.9	TSL:1 MANE Select	c.-29-10519G>A		intron	N/A	ENSP00000348381.4
	ADD3	ENST00000277900.12	TSL:1	c.-29-10519G>A		intron	N/A	ENSP00000277900.8
	ADD3	ENST00000360162.7	TSL:1	c.-29-10519G>A		intron	N/A	ENSP00000353286.3

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53405 AN: 151566 Hom.: 14219 Cov.: 31

Gnomad AFR AF: 0.740

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.315

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

GnomAD4 genome AF: 0.353 AC: 53515 AN: 151682 Hom.: 14265 Cov.: 31 AF XY: 0.352 AC XY: 26105 AN XY: 74070

African (AFR) AF: 0.740 AC: 30607 AN: 41352

American (AMR) AF: 0.208 AC: 3174 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 796 AN: 3464

East Asian (EAS) AF: 0.407 AC: 2101 AN: 5168

South Asian (SAS) AF: 0.523 AC: 2511 AN: 4802

European-Finnish (FIN) AF: 0.150 AC: 1563 AN: 10426

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.175 AC: 11890 AN: 67922

Other (OTH) AF: 0.317 AC: 669 AN: 2110

Alfa AF: 0.262 Hom.: 1458

Bravo AF: 0.366

Asia WGS AF: 0.487 AC: 1694 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.0
DANN	Benign	0.56
PhyloP100		-0.17
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: rs2501575; hg19: chr10-111849864;