10-110088062-T-C

Variant names:

• chr10-110088062-T-C
• rs6584970
• NM_016824.5:c.-29-12563T>C

Variant summary

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

The NM_016824.5(ADD3):​c.-29-12563T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 152,106 control chromosomes in the GnomAD database, including 8,670 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 0.28 (8670 hom., cov: 32)
• Consequence: ADD3 NM_016824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.563 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.-29-12563T>C		intron	N/A	NP_058432.1
	ADD3	NM_001320591.2		c.-29-12563T>C		intron	N/A	NP_001307520.1
	ADD3	NM_001320592.2		c.-29-12563T>C		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.-29-12563T>C		intron	N/A	ENSP00000348381.4
	ADD3	ENST00000277900.12	TSL:1	c.-29-12563T>C		intron	N/A	ENSP00000277900.8
	ADD3	ENST00000360162.7	TSL:1	c.-29-12563T>C		intron	N/A	ENSP00000353286.3

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41837 AN: 151988 Hom.: 8647 Cov.: 32

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.0844

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.255

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

GnomAD4 genome AF: 0.276 AC: 41915 AN: 152106 Hom.: 8670 Cov.: 32 AF XY: 0.274 AC XY: 20361 AN XY: 74376

African (AFR) AF: 0.569 AC: 23587 AN: 41434

American (AMR) AF: 0.166 AC: 2538 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 570 AN: 3466

East Asian (EAS) AF: 0.404 AC: 2091 AN: 5174

South Asian (SAS) AF: 0.391 AC: 1882 AN: 4814

European-Finnish (FIN) AF: 0.0844 AC: 896 AN: 10614

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9645 AN: 67990

Other (OTH) AF: 0.257 AC: 544 AN: 2116

Alfa AF: 0.223 Hom.: 877

Bravo AF: 0.291

Asia WGS AF: 0.428 AC: 1490 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.0
DANN	Benign	0.41
PhyloP100		-1.3
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: rs6584970; hg19: chr10-111847820;