10-110130021-G-A

Variant names:

• chr10-110130021-G-A
• rs11194997
• NM_016824.5:c.1609-342G>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.1609-342G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,016 control chromosomes in the GnomAD database, including 14,286 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 (14286 hom., cov: 32)
• Consequence: ADD3 NM_016824.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.398
• Publications: 3 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.737 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.1609-342G>A		intron	N/A	NP_058432.1
	ADD3	NM_001320591.2		c.1609-342G>A		intron	N/A	NP_001307520.1
	ADD3	NM_001320592.2		c.1609-342G>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.1609-342G>A		intron	N/A	ENSP00000348381.4
	ADD3	ENST00000277900.12	TSL:1	c.1609-342G>A		intron	N/A	ENSP00000277900.8
	ADD3	ENST00000360162.7	TSL:1	c.1609-342G>A		intron	N/A	ENSP00000353286.3

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52980 AN: 151896 Hom.: 14239 Cov.: 32

Gnomad AFR AF: 0.743

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.349 AC: 53093 AN: 152016 Hom.: 14286 Cov.: 32 AF XY: 0.349 AC XY: 25912 AN XY: 74316

African (AFR) AF: 0.744 AC: 30846 AN: 41474

American (AMR) AF: 0.208 AC: 3182 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 786 AN: 3468

East Asian (EAS) AF: 0.387 AC: 2007 AN: 5184

South Asian (SAS) AF: 0.523 AC: 2521 AN: 4824

European-Finnish (FIN) AF: 0.138 AC: 1450 AN: 10538

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11438 AN: 67946

Other (OTH) AF: 0.313 AC: 662 AN: 2114

Alfa AF: 0.303 Hom.: 3442

Bravo AF: 0.364

Asia WGS AF: 0.479 AC: 1663 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.4
DANN	Benign	0.36
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11194997; hg19: chr10-111889779;