NM_016824.5:c.-29-13696A>G

Variant names:

• chr10-110086929-A-G
• rs2501577
• NM_016824.5:c.-29-13696A>G

Variant summary

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

The NM_016824.5(ADD3):​c.-29-13696A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 152,192 control chromosomes in the GnomAD database, including 15,769 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 0.37 (15769 hom., cov: 32)
• Consequence: ADD3 NM_016824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.295
• Publications: 7 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADD3	NM_016824.5	c.-29-13696A>G		intron_variant	Intron 1 of 14	ENST00000356080.9	NP_058432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADD3	ENST00000356080.9	c.-29-13696A>G		intron_variant	Intron 1 of 14	1	NM_016824.5	ENSP00000348381.4

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55549 AN: 152074 Hom.: 15719 Cov.: 32

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.322

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

GnomAD4 genome AF: 0.366 AC: 55662 AN: 152192 Hom.: 15769 Cov.: 32 AF XY: 0.364 AC XY: 27122 AN XY: 74412

African (AFR) AF: 0.784 AC: 32541 AN: 41494

American (AMR) AF: 0.214 AC: 3278 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 805 AN: 3472

East Asian (EAS) AF: 0.407 AC: 2107 AN: 5178

South Asian (SAS) AF: 0.527 AC: 2537 AN: 4818

European-Finnish (FIN) AF: 0.148 AC: 1570 AN: 10602

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11932 AN: 68020

Other (OTH) AF: 0.324 AC: 686 AN: 2116

Alfa AF: 0.295 Hom.: 1781

Bravo AF: 0.382

Asia WGS AF: 0.491 AC: 1706 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	3.4
DANN	Benign	0.50
PhyloP100		0.29
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: rs2501577; hg19: chr10-111846687; COSMIC: COSV53322721;